Systems and method or uses of ablating cardiac tissue

ABSTRACT

The subject of this disclosure is devices, systems, and uses thereof to treat a plurality of patients for paroxysmal atrial fibrillation. The solution can include delivering a multi-electrode radiofrequency balloon catheter and a multi-electrode diagnostic catheter to one or more targeted pulmonary veins; ablating tissue of the one or more targeted pulmonary veins using the multi-electrode radiofrequency balloon catheter; diagnosing the one or more targeted pulmonary veins using the multi-electrode diagnostic catheter; and achieving at least one of a predetermined clinical effectiveness and acute effectiveness of the method or use based on use of the multi-electrode radiofrequency balloon catheter and the multi-electrode diagnostic catheter in the isolation of the one or more targeted pulmonary veins.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 16/569,585, filed on Sep. 12, 2019, which is a continuation inpart application of U.S. patent application Ser. No. 14/578,807, filedon Dec. 22, 2014. U.S. patent application Ser. No. 14/578,807 claimspriority to U.S. provisional patent application No. 62/731,525 (AttorneyDocket No. BIO6040USPS1; 253757.000003) filed Sep. 14, 2018, U.S.provisional patent application No. 62/754,275 (Attorney Docket:BIO6039USPSP1; 253757.000002) filed Nov. 1, 2018, U.S. provisionalpatent application No. 62/771,896 (Attorney Docket No. BIO6079USPSP1;253757.000004) filed Nov. 27, 2018, and to U.S. provisional patentapplication No. 62/873,636 (Attorney Docket No. BIO6039USPSP2;253757.000008) filed Jul. 12, 2019, U.S. provisional patent applicationNo. 62/886,729 (Attorney Docket No. BIO6039USPSP3; 253757.000013) filedAug. 14, 2019, and to U.S. provisional patent application No. 62/889,471(Attorney Docket No. BIO6039USPSP4; 253757.000014) filed Aug. 20, 2019.

The contents of these United States non-provisional patent applicationsand provisional patent applications are incorporated herein by referencein their entirety as if set forth verbatim.

FIELD

This disclosure relates to medical devices.

BACKGROUND

Cardiac arrhythmias, such as atrial fibrillation (AF), occur whenregions of cardiac tissue abnormally conduct electric signals toadjacent tissue. This disrupts the normal cardiac cycle and causesasynchronous rhythm. Certain procedures exist for treating arrhythmia,including surgically disrupting the origin of the signals causing thearrhythmia and disrupting the conducting pathway for such signals. Byselectively ablating cardiac tissue by application of energy via acatheter, it is sometimes possible to cease or modify the propagation ofunwanted electrical signals from one portion of the heart to another.The ablation process destroys the unwanted electrical pathways byformation of non-conducting lesions.

With this in mind, it is understood that AF is the most common sustainedarrhythmia in humans. It affects anywhere from 0.4% to 1% of the generalpopulation and increases in prevalence with age to approximately 10% inpatients over 80 years of age. The primary clinical benefit of AFablation is improvement in quality of life resulting from theelimination of arrhythmia-related symptoms such as palpitations,fatigue, or effort intolerance.

However, due to variances in human anatomy, ostia and tubular regions inthe heart come in all sizes. Thus, conventional balloon or inflatablecatheters may not have necessary flexibility to accommodate differentshapes and sizes while having sufficient structural support foreffective circumferential contact with tissue. In particular, ablationelectrodes that provide greater surface contact may lack sufficientflexibility. Moreover, delicate wires such as those of electrode leadwires and/or thermocouple wires and their solder joints need support andprotection from breakage and damage during both assembly and use in thepatient's body. Additionally, because the balloon configuration isradially symmetrical and multiple electrode elements surround theballoon configuration, determining the orientation of the balloonelectrode assembly under fluoroscopy has also posed challenges.

SUMMARY

Accordingly, the inventors of this disclosure have recognized that thereis a need for a balloon or a catheter having an inflatable member withcontact electrodes that can contact more tissue area while remainingsufficiently flexible to accommodate different anatomy and the tighterspace constraints of an ostium and a pulmonary vein. The inventors haverecognized a need for a balloon catheter to carry an electrode assemblywith adaptations for the ostium and pulmonary vein that can bemanufactured from a generic flexible circuit. There is a further desirefor a balloon catheter capable of multiple functions includingdiagnostic and therapeutic functions, such as ablation, pacing,navigation, temperature sensing, electropotential sensing and impedancesensing, and be adaptive for use with other catheters, including a lassocatheter or a focal catheter.

The solution of this disclosure resolves these and other issues of theart.

The subject of this disclosure is the use of a multi-electrode RFballoon catheter and a multi-electrode diagnostic catheter for thetreatment of paroxysmal atrial fibrillation (PAF) to achieve at leastone of a predetermined clinical effectiveness and acute effectivenessfor a predetermined population size. The inventors believe that thereare theoretical advantages of a multi-electrode RF balloon catheter inconjunction with the multi-electrode diagnostic catheter of thisdisclosure, which includes high probability of single-shot pulmonaryvein isolation with minimal collateral damage to non-pulmonary veinstructures, but without the drawbacks of excessive heating or cooling ofthe surrounding tissue. In some examples, a multi-electrode RF balloonof the multi-electrode RF balloon catheter is configured to deliverdirectionally-tailored energy using multiple electrodes, optimizingsafety and/or efficacy. In particular, examples of this disclosure aresuited for isolation of the atrial pulmonary veins in treatment ofsubjects with paroxysmal atrial fibrillation.

In some examples, a method or use is disclosed to treat a plurality ofpatients for paroxysmal atrial fibrillation. The method or use isdisclosed to treat a plurality of patients for paroxysmal atrialfibrillation, the method comprising the steps of administering a heparinbolus prior to transseptal puncture; providing transseptal access for amulti-electrode radiofrequency balloon catheter and a mapping catheteracross a septum; using a lasso catheter for at least one septumpuncture; irrigating, by the balloon catheter, continuously at or aboutall targeted veins; confirming activated clotting time betweenapproximately about 350 and 400 seconds prior to inserting the ballooncatheter into a left atrium; and performing pulmonary vein ablation withthe balloon catheter with a maximum temperature setting of the ballooncatheter being approximately about 55° C. thereby achieving at least oneof a predetermined clinical effectiveness and acute effectiveness of themulti-electrode radiofrequency balloon catheter in the isolation of thetargeted pulmonary veins, during and approximately 3 months afterablation.

In some examples, the step of performing pulmonary vein isolationcomprises ablating tissue of the targeted veins with one or more of aplurality of independently controlled electrodes of the ballooncatheter.

In some examples, for a patient population, silent cerebral lesionincidences at discharge are approximately about 10% of the patients.

In some examples, for a patient population, silent cerebral lesionincidences at discharge are approximately about 10% of the patients.

In some examples, the method includes reducing silent cerebral lesionincidences at discharge by approximately about 50% for the patients incomparison to a clinically approved RF balloon catheter performingpulmonary vein isolation according to a different ablation workflow.

In some examples, the method includes reducing incidence of minor strokefor the patients in comparison to a clinically approved RF ballooncatheter performing pulmonary vein isolation according to a differentablation workflow.

In some examples, the method includes achieving a mean activatedclotting time of approximately about 380 seconds for all patients.

In some examples, the method includes increasing mean activated clottingtime by approximately about 36 seconds for all patients in comparison toa clinically approved RF balloon catheter performing pulmonary veinisolation according to a different ablation workflow.

In some examples, the method includes increasing mean activated clottingtime by approximately about 10% for all patients in comparison to aclinically approved RF balloon catheter performing pulmonary veinisolation according to a different ablation workflow.

In some examples, the method includes achieving a mean activatedclotting time of approximately about 376 seconds for all patients withsilent cerebral lesion.

In some examples, the method includes increasing mean activated clottingtime by approximately about 27 seconds for all patients with silentcerebral lesion in comparison to a clinically approved RF ballooncatheter performing pulmonary vein isolation according to a differentablation workflow.

In some examples, the method includes increasing mean activated clottingtime by approximately about 8% for all patients with silent cerebrallesion in comparison to a clinically approved RF balloon catheterperforming pulmonary vein isolation according to a different ablationworkflow.

In some examples, the method includes achieving a mean activatedclotting time of approximately about 380 seconds for all patientswithout silent cerebral lesion.

In some examples, the method includes increasing mean activated clottingtime by approximately about 38 seconds for all patients without silentcerebral lesion in comparison to a clinically approved RF ballooncatheter performing pulmonary vein isolation according to a differentablation workflow.

In some examples, the method includes increasing mean activated clottingtime by approximately about 11% for all patients without silent cerebrallesion in comparison to a clinically approved RF balloon catheterperforming pulmonary vein isolation according to a different ablationworkflow.

In some examples, a patient population for the method is at leastapproximately about 98 patients.

In some examples, a patient population for the method is at leastapproximately about 40 patients.

In some examples, a method or use is disclosed to treat a plurality ofpatients for paroxysmal atrial fibrillation. The method or use caninclude delivering a multi-electrode radiofrequency balloon catheter anda multi-electrode diagnostic catheter to one or more targeted pulmonaryveins; ablating tissue of the one or more targeted pulmonary veins usingthe multi-electrode radiofrequency balloon catheter; diagnosing the oneor more targeted pulmonary veins using the multi-electrode diagnosticcatheter; and achieving at least one of a predetermined clinicaleffectiveness and acute effectiveness of the procedure based on use ofthe multi-electrode radiofrequency balloon catheter and themulti-electrode diagnostic catheter in the isolation of the one or moretargeted pulmonary veins.

In some examples, the acute effectiveness is defined by confirming ifthere is an entrance block in all targeted pulmonary veins afteradenosine and/or isoproterenol challenge.

In some examples, the acute effectiveness is further defined by successgreater than 90% for the plurality of patients.

In some examples, the acute effectiveness is further defined by successgreater than 95% for the plurality of patients.

In some examples, a Type-1 error rate for power the acute effectivenessand the clinical effectiveness of all targeted veins are controlled atapproximately a 5% level. The method or use can include determiningwhether the procedure is clinically successful for the plurality ofpatients if both the acute effectiveness and the clinical effectivenessindications are controlled at approximately the 5% level.

In some examples, the acute effectiveness is at least 80% for theplurality of patients being at least 80 patients, 130 patients, and/or230 patients.

In some examples, the acute effectiveness is further defined byconfirming if there is an entrance block in all targeted pulmonary veinsafter adenosine and/or isoproterenol challenge using a focal ablationcatheter.

In some examples, the acute effectiveness is further defined byconfirming if there is an entrance block in all targeted pulmonary veinsafter adenosine and/or isoproterenol challenge without using a focalablation catheter.

In some examples, the procedure is administered on the plurality ofpatients diagnosed with symptomatic paroxysmal atrial fibrillation.

In some examples, the predetermined effectiveness rate is defined by anaverage number of RF applications per patient and RF time required toisolate all pulmonary veins. the step of diagnosing further comprises:electrophysiological mapping of the heart.

In some examples, the multi-electrode diagnostic catheter furthercomprises a high torque shaft with a halo-shaped tip section containinga plurality of pairs of electrodes visible under fluoroscopy.

In some examples, the predetermined acute effectiveness is defined byulceration being absent in the plurality of patients after theprocedure.

In some examples, the predetermined acute effectiveness is defined by acomplication rate of approximately 13% or fewer of the plurality ofpatients experiencing esophageal erythema after the procedure.

In some examples, the predetermined acute effectiveness is defined by acomplication rate of approximately 25% or fewer of the plurality ofpatients experiencing new asymptomatic cerebral embolic lesions afterthe procedure.

In some examples, the predetermined acute effectiveness is defined by acomplication rate of approximately 20% or fewer of the plurality ofpatients experiencing new asymptomatic cerebral embolic lesions afterthe procedure.

In some examples, wherein the predetermined acute effectiveness isdefined by a complication rate of approximately 5-9% or fewer of theplurality of patients experiencing a primary adverse event byapproximately 7 or more days after the procedure.

In some examples, inclusion criteria for the plurality of patientsincludes a diagnosis with symptomatic paroxysmal atrial fibrillation anda patient capability to comply with uninterrupted per-protocolanticoagulation requirements.

In some examples, the predetermined acute effectiveness is defined by atotal procedure time.

In some examples, a population size for the predetermined success rateis at least 80 patients, 130 patients, 180 patients, and/or 230patients.

In some examples, the predetermined acute effectiveness is defined by atotal RF application time.

In some examples, the predetermined acute effectiveness is defined by atotal dwell time of the multi-electrode radiofrequency balloon catheter.

In some examples, the predetermined acute effectiveness is defined by atotal time to isolate all targeted pulmonary veins.

In some examples, the predetermined acute effectiveness is defined by anumber and a total time of applications by the multi-electroderadiofrequency balloon catheter per location of all targeted pulmonaryveins.

In some examples, the predetermined acute effectiveness is defined by anumber and a total time of applications by the multi-electroderadiofrequency balloon catheter per patient.

In some examples, the predetermined acute effectiveness is defined by anumber and a total time of applications by the multi-electroderadiofrequency balloon catheter per targeted vein.

In some examples, multi-electrode radiofrequency balloon cathetercomprises a compliant balloon with a plurality of electrodes bondedconfigured to deliver RF energy to tissue of the pulmonary vein andsense temperature at each electrode.

In some examples, clinical effectiveness is defined by an incidence ofearly onset of one or more adverse events within a predetermined time ofthe procedure being implemented.

In some examples, the predetermined time is at least 7 days.

In some examples, the one or more adverse events comprise: death,atrio-esophageal fistula, myocardial infarction, cardiactamponade/perforation, thromboembolism, stroke, TIA (Transient IschemicAttack), phrenic nerve paralysis, pulmonary vein stenosis, and majorvascular access bleeding.

In some examples, the one or more adverse events comprise: incidence ofindividual adverse events from a primary composite; incidence of seriousadverse device effect; incidence of serious adverse events within 7days, at least 7-30 days, and at least 30 days following the procedure;incidence of non-serious adverse events; incidence of pre-andpost-ablation asymptomatic and symptomatic cerebral emboli as determinedby MRI evaluation; and frequency, anatomic location, and size (diameterand volume) of cerebral emboli by MRI evaluations at baseline,post-ablation and during follow-up.

In some examples, the one or more adverse events for approximately 8% ofthe plurality of patients, the one or more adverse events comprising:NIHSS (National Institute of Health Stroke Scale) scores at baseline,post-ablation and during follow-up; a summary of MoCA (MontrealCognitive Assessment) and mRS (Modified Ranking Scale) scores atbaseline, 1 month and during further follow-up; a rate ofhospitalization for cardiovascular events; a percentage (%) of pulmonaryvein isolation touch-up by focal catheter among the one or more targetedveins; a percentage (%) of subjects with use of focal catheter ablationsfor non-PV triggers; a percentage (%) of subjects with freedom fromdocumented symptomatic atrial fibrillation (AF), atrial tachycardia(AT), or atypical (left side) atrial flutter (AFL) episodes(episodes >30 seconds on arrhythmia monitoring device from day 91 to180); a percentage (%) of subjects with freedom from documented atrialfibrillation (AF), atrial tachycardia (AT), or atypical (left side)atrial flutter (AFL); one or more episodes that endure for 30 or moreseconds on an arrhythmia monitoring device from day 91 to 180 followingthe procedure; and one or more procedural parameters including totalprocedure and ablation time, balloon dwell time, RF application time, anumber of RF applications, fluoroscopy time and dose.

In some examples, the acute safety rate includes complication rates of10% or less and is defined by incidence of asymptomatic cerebral emboliclesions at a discharge magnetic resonance imaging (MRI).

In some examples, the acute effectiveness rate includes complicationrates of approximately 0% and is defined by existence of esophagealinjury erythema.

In some examples, the acute effectiveness rate is 100% and is defined byelectrically isolating all targeted pulmonary veins without use of afocal ablation catheter.

In some examples, the acute effectiveness rate is defined by a freedomfrom documented atrial fibrillation, atrial tachycardia, or atypicalatrial flutter episodes based on electrocardiographic data through aneffectiveness evaluation period (1 year).

In some examples, the acute effectiveness rate is defined by pulmonaryvein isolation touch-up by a focal catheter among all targeted pulmonaryveins.

In some examples, the predetermined clinical effectiveness rate isdefined by 10% or less complication rates related to incidence ofpost-ablation symptomatic and asymptomatic cerebral emboli as comparedto pre-ablation.

In some examples, the multi-electrode diagnostic catheter is configuredfor electrophysiological recording and stimulation of the atrial regionof the heart and is used in conjunction with the multi-electroderadiofrequency balloon catheter.

In some examples, a method or use of administering a procedure to treata plurality of patients for paroxysmal atrial fibrillation. The methodor use includes delivering a multi-electrode radiofrequency ballooncatheter and a multi-electrode diagnostic catheter to one or moretargeted pulmonary veins; and ablating tissue of all targeted pulmonaryveins using the multi-electrode radiofrequency balloon catheter;diagnosing all targeted pulmonary veins using the multi-electrodediagnostic catheter; and achieving a predetermined rate of adverseevents, using the multi-electrode radiofrequency balloon catheter andthe multi-electrode diagnostic catheter in the isolation of all targetedpulmonary veins, during and approximately 6 months after the procedure.

In some examples, a method or use of treating a plurality of patientsfor paroxysmal atrial fibrillation. The method or use includesevaluating a number and size of all targeted pulmonary veins and anatomyof the left atrial; puncturing the transseptal; selectively positioninga multi-electrode esophageal temperature monitoring device in thevasculature with respect to all targeted pulmonary veins; selectivelypositioning a multi-electrode radiofrequency balloon catheter in thevasculature with respect to all targeted pulmonary veins; selectivelypositioning a multi-electrode diagnostic catheter in the vasculaturewith respect to all targeted pulmonary veins; ablating tissue of alltargeted pulmonary veins using the multi-electrode radiofrequencyballoon catheter; confirming isolation of all targeted pulmonary veinsusing the multi-electrode diagnostic catheter; confirming existence ofan entrance block in all targeted pulmonary veins; achieving apredetermined clinical effectiveness and/or acute effectiveness of theprocedure, based on the confirmed existence of the entrance block,regarding the isolation of all targeted pulmonary veins following theprocedure.

In some examples, mapping all targeted pulmonary veins using thediagnostic catheter.

In some examples, exclusion criteria for the plurality of patientscomprises at least one of the following: atrial fibrillation secondaryto electrolyte imbalance, thyroid disease, or reversible or non-cardiaccause; previous surgical or catheter ablation for atrial fibrillation;anticipated to receive ablation outside all targeted pulmonary veinsostia and CTI region; previously diagnosed with persistent, longstandingatrial fibrillation and/or continuous atrial fibrillation >7 days,or >48 hrs terminated by cardioversion; any percutaneous coronaryintervention (PCI) within the past 2 months; valve repair or replacementand presence of a prosthetic valve; any carotid stenting orendarterectomy; coronary artery bypass grafting, cardiac surgery,valvular cardiac surgical or percutaneous procedure within the past 6months; documented left atrium thrombus on baseline imaging; LA anteroposterior diameter greater than 50 mm; any pulmonary vein with adiameter greater than or equal to 26 mm; left ventricular ejectionfraction less than 40%; contraindication to anticoagulation; history ofblood clotting or bleeding abnormalities; myocardial infarction withinthe past 2 months; documented thromboembolic event within the past 12months; rheumatic heart disease; awaiting cardiac transplantation orother cardiac surgery within the next 12 months; unstable angina; acuteillness or active systemic infection or sepsis; diagnosed atrial myxomaor interatrial baffle or patch; presence of implanted pacemaker,implantable cardioverter defibrillator, tissue-embedded, oriron-containing metal fragments; significant pulmonary disease or anyother disease or malfunction of the lungs or respiratory system thatproduces chronic symptoms; significant congenital anomaly; pregnancy orlactating; enrollment in an investigational study evaluating anotherdevice, biologic, or drug; pulmonary vein stenosis; presence ofintramural thrombus, tumor or other abnormality that precludes vascularaccess, or manipulation of the catheter; presence of an IVC filter;presence of a condition that precludes vascular access; life expectancyor other disease processes likely to limit survival to less than 12months; contraindication to use of contrast agents for MRI; presence ofiron-containing metal fragments in the patient; or unresolvedpre-existing neurological deficit.

In some examples, the multi-electrode radiofrequency balloon catheterincludes a compliant balloon with a plurality of electrodes configuredto deliver RF energy to tissue of all targeted pulmonary veins and sensetemperature at each electrode. In some examples, the plurality ofelectrodes is oriented circularly to circumferentially contact with anostia of the pulmonary vein. In some examples, the method or useincludes using the plurality of electrodes for visualization,stimulation, recording, and ablation. In some examples, each electrodeis configured so an amount of power delivered to each electrode iscontrolled independently. In some examples, the multi-electroderadiofrequency balloon catheter further comprises a proximal handle, adistal tip, and a middle section disposed therebetween. In someexamples, the proximal handle is a deflection thumb knob allowing forunidirectional deflection, a balloon advancement mechanism, and a luerfitting for balloon inflation and irrigation. In some examples, themulti-electrode radiofrequency balloon catheter further comprises ahigh-torque shaft configured to be rotated to facilitate accuratepositioning of the catheter tip to a desired; and a unidirectionalbraided deflectable tip section.

In some examples, the method or use also includes controlling irrigationto the multi-electrode radiofrequency balloon catheter with anirrigation pump.

In some examples, the method or use also includes administeringuninterrupted anticoagulation therapy at least 1 month prior to theprocedure.

In some examples, if the patient is receiving warfarin/coumadin therapy,the patient must have an international normalized ratio (INR) ≥2 for atleast 3 weeks prior to the procedure.

In some examples, if the patient is receiving warfarin/coumadin therapy,the patient must be confirmed to have an international normalized ratio(INR) ≥2 within 48 hours pre-procedure.

In some examples, the method or use also includes continuinganticoagulation therapy prior to the procedure.

In some examples, the method or use also includes administering atransseptal puncture; confirming an activated clotting time target of≥350 sec. prior to inserting the multi-electrode radiofrequency ballooncatheter into the left atrium and maintaining throughout the procedure;introducing the multi-electrode radiofrequency balloon catheter;introducing of a multi-electrode circular diagnostic catheter; ablatingthe pulmonary vein with the multi-electrode radiofrequency ballooncatheter; determining in real time pulmonary vein isolation with themulti-electrode circular diagnostic catheter; and confirming whether anentrance is blocked in the pulmonary vein.

In some examples, the method or use also includes the multi-electrodecircular diagnostic catheter comprises: an elongated body having alongitudinal axis; a distal assembly distal the elongated body, thedistal assembly having a helical form comprising a proximal loop and adistal loop, and a shape-memory support member extending through atleast the proximal loop, the proximal loop and the distal loop beingoriented obliquely at an angle relative to the longitudinal axis of theelongated body; at least one irrigated ablation ring electrode mountedon the proximal loop; a control handle proximal the elongated body; anda contraction wire having a proximal end in the control handle and adistal end anchored in the proximal loop, the control handle including afirst control member configured to actuate the contraction wire tocontract the proximal loop, wherein the proximal loop has a firstflexibility and the distal loop has a second flexibility, and the secondflexibility is greater than the first flexibility.

In some examples, a method or use of treating a plurality of patientsfor paroxysmal atrial fibrillation by applying energy to tissue of asubject's heart proximate to an esophagus, phrenic nerve, or lung, themethod or use comprising the steps of achieving at least one of apredetermined clinical effectiveness and acute effectiveness of theprocedure based on use of a multi-electrode radiofrequency ballooncatheter and a multi-electrode diagnostic catheter in the isolation ofthe one or more targeted pulmonary veins by positioning an expandablemember proximate to the left atrium, the expandable member of themulti-electrode radiofrequency balloon catheter having a longitudinalaxis and including a plurality of electrodes disposed about thelongitudinal axis, each electrode capable of being energizedindependently, the plurality of electrodes including a first electrodehaving a first radiopaque marker and a second electrode having a secondradiopaque marker different from the first radiopaque marker; viewing animage of the expandable member as well as the first and secondradiopaque markers in the left atrium; determining an orientation of thefirst and second radiopaque markers with respect to a portion of theleft atrium closest to the esophagus, phrenic nerve, or lung, of thesubject; moving one of the first and second radiopaque markers to aportion of the left atrium closest to the esophagus, phrenic nerve orlung; energizing one or more electrodes indexed to the one of theradiopaque markers proximate the portion close to the esophagus, phrenicnerve, or lung, at a lower energization setting as compared to otherelectrodes to create a transmural lesion in the left atrium with littleor no effect to adjacent anatomical structures; andelectrophysiologically recording and stimulating the atrial region ofthe tissue proximate to the esophagus, phrenic nerve, or lung using themulti-electrode diagnostic catheter.

In some examples, a multi-electrode RF balloon catheter is alsodisclosed for the treatment of drug refractory atrial fibrillation in aclinically effective and/or clinically safe manner for a predeterminedpopulation size.

In some examples, a clinically effective device is disclosed to treatatrial fibrillation in a group of patients. The device can include anend probe coupled to a tubular member that extends along a longitudinalaxis from a proximal portion to a distal portion. The end probe caninclude a first expandable membrane coupled to the tubular member; aplurality of electrodes disposed generally equiangularly about thelongitudinal axis on an outer surface of the first expandable membrane;at least one wire connected each of the plurality of electrodes, the atleast one wire of each electrode extending from the first expandablemembrane toward the tubular member; and a second expandable membranethat encapsulates a portion of the at least one wire between the secondexpandable membrane and the first expandable membrane. The device canachieve a predetermined effectiveness rate of pulmonary vein isolationin the group of patients.

In some examples, a clinically effective device is disclosed toadminister a procedure for cardiac electrophysiological ablation ofpulmonary veins of the atria and treatment of drug refractory recurrentsymptomatic pulmonary atrial fibrillation. The device can include an endprobe coupled to a tubular member that extends along a longitudinal axisfrom a proximal portion to a distal portion. The end probe can include afirst expandable membrane coupled to the tubular member; a plurality ofelectrodes disposed generally equiangularly about the longitudinal axison an outer surface of the first expandable membrane; at least one wireconnected each of the plurality of electrodes, the at least one wire ofeach electrode extending from the first expandable membrane toward thetubular member; and a second expandable membrane that encapsulates aportion of the at least one wire between the second expandable membraneand the first expandable membrane so that each of the plurality ofelectrodes is independently controlled to achieve a predeterminedeffectiveness rate of pulmonary vein isolation.

In some examples, a clinically effective device is disclosed toadminister a procedure for cardiac electrophysiological ablation ofpulmonary veins of the atria and treatment of drug refractory recurrentsymptomatic pulmonary atrial fibrillation. The device can include an endprobe coupled to a tubular member that extends along a longitudinal axisfrom a proximal portion to a distal portion. The end probe can include afirst expandable membrane coupled to the tubular member; a plurality ofelectrodes disposed generally equiangularly about the longitudinal axison an outer surface of the first expandable membrane; at least one wireconnected each of the plurality of electrodes, the at least one wire ofeach electrode extending from the first expandable membrane toward thetubular member; and a second expandable membrane that encapsulates aportion of the at least one wire between the second expandable membraneand the first expandable membrane so that each of the plurality ofelectrodes is independently controlled to achieve pulmonary veinisolation and at least a 97% safety endpoint within seven (7) days ofsuccessful pulmonary vein isolation.

In some examples, a clinically effective device is disclosed toadminister a procedure for cardiac electrophysiological ablation ofpulmonary veins of the atria and treatment of drug refractory recurrentsymptomatic pulmonary atrial fibrillation. The device can include an endprobe coupled to a tubular member that extends along a longitudinal axisfrom a proximal portion to a distal portion. The end probe can include afirst expandable membrane coupled to the tubular member; a plurality ofelectrodes disposed generally equiangularly about the longitudinal axison an outer surface of the first expandable membrane; at least one wireconnected each of the plurality of electrodes, the at least one wire ofeach electrode extending from the first expandable membrane toward thetubular member; and a second expandable membrane that encapsulates aportion of the at least one wire between the second expandable membraneand the first expandable membrane so that each of the plurality ofelectrodes is independently controlled to achieve pulmonary veinisolation and at least a 90% safety endpoint within seven (7) days ofsuccessful pulmonary vein isolation.

In some examples, the predetermined effectiveness rate includescomplication rates of 10% or less and is defined by existence ornon-existence of asymptomatic cerebral embolic lesions at a dischargemagnetic resonance imaging (MRI).

In some examples, the predetermined effectiveness rate includescomplication rates of approximately 0% and is defined by existence ornon-existence of esophageal injury erythema.

In some examples, the predetermined effectiveness rate is approximately100% and is defined by electrically isolating all targeted pulmonaryveins without use of a focal ablation catheter.

In some examples, the predetermined effectiveness rate is defined by afreedom from documented atrial fibrillation, atrial tachycardia, oratypical atrial flutter episodes based on electrocardiographic datathrough an effectiveness evaluation period. In some examples, theeffectiveness evaluation period is approximately one year.

In some examples, the predetermined effectiveness rate is defined bypulmonary vein isolation touch-up by a focal catheter among all targetedpulmonary veins.

In some examples, the predetermined effectiveness rate is defined byusing focal catheter ablation for non-PV triggers during the indexprocedure.

In some examples, the predetermined effectiveness rate comprises along-term effectiveness rate.

In some examples, the predetermined effectiveness rate is defined by anaverage number of Radio-Frequency applications per patient andRadio-Frequency time required to isolate all pulmonary veins.

In some examples, the predetermined effectiveness rate is defined by anaverage number of Radio-Frequency applications per vein andRadio-Frequency time required to isolate common pulmonary veins.

In some examples, the predetermined effectiveness rate is defined by anaverage number of Radio-Frequency applications per patient andRadio-Frequency time required to isolate common pulmonary veins.

In some examples, the predetermined effectiveness rate is defined bydetermining incidence of complication rates being 10% or less ofpost-ablation symptomatic and asymptomatic cerebral emboli as comparedto pre-ablation.

In some examples, the predetermined effectiveness rate is defined byevaluating a presence of emboli-associated neurological deficits by atleast one of NIHSS and mRS assessments.

In some examples, the end probe is configured for use in catheter-basedcardiac electrophysiological mapping of the atria.

In some examples, the end probe is configured for cardiac ablation.

In some examples, the end probe comprises: the plurality of electrodesbonded to the first expandable membrane and configured to deliverRadio-Frequency energy to tissue of the pulmonary vein and sensetemperature at each electrode.

In some examples, the plurality of electrodes is oriented circularly tocircumferentially contact with an ostia of the pulmonary vein.

In some examples, the device is further configured for using theplurality of electrodes for visualization, stimulation, recording, andablation.

In some examples, each electrode is configured so an amount of powerdelivered to each electrode is controlled independently.

In some examples, the end probe further comprises a proximal handle, adistal tip, and a middle section disposed therebetween.

In some examples, the proximal handle is a deflection thumb knoballowing for unidirectional deflection, a balloon advancement mechanism,and a luer fitting for balloon inflation and irrigation.

In some examples, the end probe further includes a high-torque shaftconfigured to be rotated to facilitate accurate positioning of thecatheter tip to a desired; and a unidirectional braided deflectable tipsection.

In some examples, the end probe further includes a first substratedisposed on the membrane, the first substrate including a firstradiopaque marker of a first form disposed thereon; and a secondsubstrate disposed on the membrane, the second substrate including asecond radiopaque marker of a second form disposed thereon, the secondform being different from the first form.

In some examples, the device further includes an irrigation pump toprovide irrigation fluid to the first expandable membrane and out of thefirst expandable membrane.

In some examples, the effectiveness evaluation period is at least 91days following a delivery of the end probe to the pulmonary vein; andablation of tissue proximate the pulmonary vein with the end probe.

In some examples, the effectiveness evaluation period is less than orequal to one year following a delivery of the end probe to the pulmonaryvein; and ablation of tissue proximate the pulmonary vein with the endprobe.

In some examples, the predetermined success rate is 60% for a populationsize of at least 40 patients.

In some examples, a population size for the predetermined success rateis at least 300 patients, 200 patients, 100 patients, or 50 patients.

In some examples, the predetermined success rate is at least 60%.

In some examples, the predetermined success rate is determined byevaluation of the patient 7 days following a delivery of the end probeto the pulmonary vein and ablation of tissue proximate the pulmonaryvein with the end probe.

In some examples, the predetermined success rate is determined byevaluation of the patient 1 month following a delivery of the end probeto the pulmonary vein; and ablation of tissue proximate the pulmonaryvein with the end probe.

In some examples, the predetermined success rate is determined byevaluation of the patient 6 months following a delivery of the end probeto the pulmonary vein; and ablation of tissue proximate the pulmonaryvein with the end probe.

In some examples, the predetermined success rate is determined byevaluation of the patient 12 months following a delivery of the endprobe to the pulmonary vein; and ablation of tissue proximate thepulmonary vein with the end probe.

In some examples, the predetermined success rate further includesconfirmation of an entrance block in the pulmonary vein after at leastone of adenosine and isoproterenol challenge.

In some examples, the patient suffering at least one of the followingevents is deemed as unsuccessful pulmonary vein isolation, including:device or procedure related death; atrio-esophageal fistula, myocardialinfarction; cardiac Tamponade/Perforation; thromboembolism;stroke/Cerebrovascular Accident (CVA); transient Ischemic Attach (TIA);phrenic Nerve Paralysis, Pulmonary Vein Stenosis; pericarditis;pulmonary Edema; major Vascular Access Complication/Bleeding; andhospitalization (initial or prolonged).

In some examples, the patient suffering at least one of the followingevents is deemed as unsuccessful pulmonary vein isolation, whereby thoseevents can include acute procedural failure; repeat ablation or surgicaltreatment for AF/AT/Atypical (left-side) AFL after the blanking period(after day 90 post index procedure); DC cardioversion for AF/AT/Atypical(left-side) AFL, continuous AF/AT/AFL on a standard 12-lead ECG even ifthe recording is less than 30 seconds in duration (after day 90 postindex procedure); a new Class I and/or Class III AAD is prescribed forAF during effectiveness evaluation period (day 91-365 post indexprocedure) or prescribed during the blanking period and continued past90 days; a previously failed Class I and/or Class III AAD (failed at orbefore screening) is taken for AF at a greater dose than the highestineffective historical dose during the effectiveness evaluation period;and amiodarone is prescribed post procedure.

In some examples, the safety endpoint is defined by a patient sufferinga primary adverse event.

In some examples, at least one risk factor for the patient is selectedat least three (3) symptomatic episodes of atrial fibrillation that lastlasting >1 minute within six (6) months before the device; at least one(1) atrial fibrillation episode electrocardiographically documentedwithin twelve (12) months prior to enrollment (e.g., electrocardiogram(ECG), Holter monitor, telemetry strip, etc.); failing at least one (1)Class I or Class III AAD as evidenced by recurrent symptomatic atrialfibrillation or intolerable side effects to the AAD; younger than 18 orolder than 75 years; secondary to electrolyte imbalance; thyroiddisease; reversible or non-cardiac cause; and previous surgical orcatheter ablation for atrial fibrillation.

In some examples, for purposes of calculating the effectiveness rate,the patient has at least one of the following risk factors: patientsknown to require ablation outside the PV ostia and CTI region;previously diagnosed with persistent or long-standing persistent atrialfibrillation and/or continuous atrial fibrillation 7 days following thedevice procedure; any percutaneous coronary intervention within the past2 months; repair or replacement or presence of a prosthetic valve; anycarotid stenting or endarterectomy within the past 6 months; coronaryartery bypass grafting, cardiac surgery or valvular cardiac surgicalprocedure within the past 6 months; documented left atrium thrombuswithin 1 day prior to the device procedure; left atrium antero posteriordiameter >50 mm; left Ventricular Ejection Fraction <40%;contraindication to anticoagulation; history of blood clotting orbleeding abnormalities; myocardial infarction within the past 2 months;documented thromboembolic event (including transient ischemic attack)within the past 12 months; Rheumatic Heart Disease; uncontrolled heartfailure or New York Heart Association (NYHA) function class III or IV;awaiting cardiac transplantation or other cardiac surgery within thenext 12 months; unstable angina; acute illness or active systemicinfection or sepsis; diagnosed atrial myxoma or presence of aninteratrial baffle or patch; presence of implanted pacemaker orimplantable cardioverter defibrillator (ICD); significant pulmonarydisease or any other disease or malfunction of the lungs or respiratorysystem that produces chronic symptoms; significant congenital anomaly;women who are pregnant; enrollment in an investigational studyevaluating another device, biologic, or drug; known pulmonary veinstenosis; presence of intramural thrombus, tumor or other abnormalitythat precludes vascular access, or manipulation of the catheter;presence of an inferior vena cava filter; presence of a condition thatprecludes vascular access; life expectancy or other disease processeslikely to limit survival to less than 12 months; presentingcontra-indication for the devices; and patient on amiodarone at any timeduring the past 3 months prior to enrollment.

In some examples, if the patient is receiving warfarin/coumadin therapy,the patient must have an international normalized ratio ≥2 for at least3 weeks prior to the procedure.

In some examples, if the patient is receiving warfarin/coumadin therapy,the patient must be confirmed to have an international normalized ratio≥2 within 48 hours pre-procedure.

In some examples, wherein anticoagulation therapy is provided prior tothe procedure.

In some examples, wherein an activated clotting time of 350-400 secondsis targeted prior to insertion of the catheter and throughout theprocedure.

In some examples, wherein an activated clotting time levels are checkedevery 15-30 minutes during the procedure to ensure an activated clottingtime target of 350-400 seconds.

In some examples, wherein the multi-electrode circular diagnosticcatheter includes an elongated body having a longitudinal axis and adistal assembly distal the elongated body. The distal assembly can havea helical form comprising a proximal loop, a distal loop, and ashape-memory support member extending through at least the proximalloop. The proximal loop and the distal loop can be oriented obliquely atan angle relative to the longitudinal axis of the elongated body; atleast one irrigated ablation ring electrode mounted on the proximalloop; a control handle proximal the elongated body; and a contractionwire having a proximal end in the control handle and a distal endanchored in the proximal loop, the control handle including a firstcontrol member configured to actuate the contraction wire to contractthe proximal loop. The proximal loop can have a first flexibility andthe distal loop has a second flexibility, and the second flexibility canbe greater than the first flexibility.

In some examples, a multi-electrode RF balloon catheter is disclosed forthe treatment of drug refractory atrial fibrillation in a clinicallyeffective and/or clinically safe manner for a predetermined populationsize.

In some examples, a method or use is disclosed for administering aprocedure for treating atrial fibrillation. The method or use caninclude delivering a multi-electrode radiofrequency balloon catheter toone or more targeted pulmonary veins; ablating tissue of the pulmonaryvein using the multi-electrode radiofrequency balloon catheter; andachieving a predetermined effectiveness rate of pulmonary veinisolation.

In some examples, the multi-electrode radiofrequency balloon catheter isconfigured for use in catheter-based cardiac electrophysiologicalmapping of the atria.

In some examples, the multi-electrode radiofrequency balloon catheter isconfigured for cardiac ablation.

In some examples, the multi-electrode radiofrequency balloon catheterhas a compliant balloon with a plurality of electrodes bonded configuredto deliver RF energy to tissue of the pulmonary vein and sensetemperature at each electrode.

In some examples, the plurality of electrodes is oriented circularly tocircumferentially contact with an ostia of the pulmonary vein.

In some examples, the method or use includes using the plurality ofelectrodes for visualization, stimulation, recording, and ablation.

In some examples, each electrode is configured so an amount of powerdelivered to each electrode is controlled independently.

In some examples, the balloon has a membrane, the balloon having adistal end and a proximal end defining a longitudinal axis, themulti-electrode radiofrequency balloon catheter includes a firstsubstrate disposed on the membrane, the first substrate including afirst radiopaque marker of a first form disposed thereon. A secondsubstrate can be disposed on the membrane, the second substrateincluding a second radiopaque marker of a second form disposed thereon,the second form being different from the first form.

In some examples, the method or use includes controlling irrigation tothe multi-electrode radiofrequency balloon catheter with an irrigationpump.

In some examples, the effectiveness evaluation period is at least 91days following the delivering the multi-electrode radiofrequency ballooncatheter to the pulmonary vein and the ablating tissue of the pulmonaryvein using the multi-electrode radiofrequency balloon catheter.

In some examples, the effectiveness evaluation period is less than orequal to one year following the delivering the multi-electroderadiofrequency balloon catheter to the pulmonary vein and the ablatingtissue of the pulmonary vein using the multi-electrode radiofrequencyballoon catheter.

In some examples, a method or use is disclosed for administering aprocedure for treating atrial fibrillation. The method or use caninclude delivering a multi-electrode radiofrequency balloon catheter toa pulmonary vein, ablating tissue of the pulmonary vein using themulti-electrode radiofrequency balloon catheter and achieving apredetermined success rate of pulmonary vein isolation.

In some examples, the predetermined success rate is determined byevaluating the patient 7 days following the delivering themulti-electrode radiofrequency balloon catheter to the pulmonary vein;and the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

In some examples, the predetermined success rate is determined byevaluating the patient 1 month, 6 months and/or 12 months following thedelivering the multi-electrode radiofrequency balloon catheter to thepulmonary vein, and the ablating tissue of the pulmonary vein using themulti-electrode radiofrequency balloon catheter.

In some examples, the success rate further includes confirming anentrance block in the pulmonary vein after at least one of adenosine andisoproterenol challenge.

In some examples, the delivering step further comprises using a focalcatheter.

In some examples, the patient suffering at least one of the followingevents is deemed as having an unsuccessful pulmonary vein isolation,including device or procedure related death, atrio-esophageal fistula,myocardial infarction, cardiac Tamponade/Perforation, thromboembolism,stroke/ Cerebrovascular Accident (CVA), transient Ischemic Attach (TIA),phrenic Nerve Paralysis, Pulmonary Vein Stenosis, pericarditis,pulmonary Edema, major Vascular Access Complication/Bleeding, andhospitalization (initial or prolonged).

In some examples, the patient suffering at least one of the followingevents is deemed as having an unsuccessful pulmonary vein isolation,having acute procedural failure, repeat ablation or surgical treatmentfor AF/atrial tachycardia (AT)/Atypical (left-side) atrial flutter (AFL)after the blanking period (after day 90 post index procedure), directcurrent (DC) cardioversion for AF/AT/Atypical (left-side) AFL,continuous AF/AT/AFL on a standard 12-lead ECG even if the recording isless than 30 seconds in duration (after day 90 post index procedure), anew Class I and/or Class III antiarrhythmic drugs (AAD) is prescribedfor AF during effectiveness evaluation period (day 91-365 post indexprocedure) or prescribed during the blanking period and continued past90 days, a previously failed Class I and/or Class III AAD (failed at orbefore screening) is taken for AF at a greater dose than the highestineffective historical dose during the effectiveness evaluation period,and amiodarone is prescribed post procedure.

In some examples, a method or use is disclosed for administering aprocedure for cardiac electrophysiological ablation of pulmonary veinsof the atria and treating drug refractory recurrent symptomaticpulmonary atrial fibrillation. The method or use can include deliveringa multi-electrode radiofrequency balloon catheter to a pulmonary vein;ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and achieving a predeterminedeffectiveness rate of pulmonary vein isolation.

In some examples, a method or use is disclosed for administering aprocedure for cardiac electrophysiological ablation of pulmonary veinsof the atria and treating drug refractory recurrent symptomaticpulmonary atrial fibrillation. The method or use can include deliveringa multi-electrode radiofrequency balloon catheter to a pulmonary vein;ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and achieving pulmonary vein isolationand at least a 97% safety endpoint within seven (7) days of successfulpulmonary vein isolation.

In some examples, a method or use is disclosed for administering aprocedure for cardiac electrophysiological ablation of pulmonary veinsof the atria and treating drug refractory recurrent symptomaticpulmonary atrial fibrillation. The method or use includes delivering amulti-electrode radiofrequency balloon catheter to a pulmonary vein,ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter, and achieving pulmonary vein isolationand at least a 90% safety endpoint within seven (7) days of successfulpulmonary vein isolation.

In some examples, the safety endpoint is defined by a patient sufferinga primary adverse event.

In some examples, at least one risk factor for the patient is selectedfrom the group of: at least three (3) symptomatic episodes of atrialfibrillation that last lasting ≥1 minute within six (6) months beforethe method or use, at least one (1) atrial fibrillation episodeelectrocardiographically documented within twelve (12) months prior toenrollment. Electrocardiographic documentation can include, but is notlimited to, electrocardiogram (ECG), Holter monitor, or telemetry strip,failing at least one (1) Class I or Class III AAD as evidenced byrecurrent symptomatic atrial fibrillation or intolerable side effects tothe AAD, age 18-75 years, secondary to electrolyte imbalance, thyroiddisease, reversible or non-cardiac cause, and previous surgical orcatheter ablation for atrial fibrillation.

In some examples, the patient has at least one risk factor selected fromthe group of: patients known to require ablation outside the PV ostiaand CTI region, previously diagnosed with persistent or long-standingpersistent atrial fibrillation and/or continuous atrial fibrillation 7days following the method or use procedure, any percutaneous coronaryintervention within the past 2 months, repair or replacement or presenceof a prosthetic valve, and any carotid stenting or endarterectomy withinthe past 6 months. Other risk factors include coronary artery bypassgrafting, cardiac surgery or valvular cardiac surgical procedure withinthe past 6 months, documented left atrium thrombus within 1 day prior tothe method or use procedure, left atrium antero posterior diameter >50mm, Left Ventricular Ejection Fraction <40%, contraindication toanticoagulation, history of blood clotting or bleeding abnormalities,myocardial infarction within the past 2 months, and documentedthromboembolic event (including transient ischemic attack) within thepast 12 months. Additional risk factors include Rheumatic Heart Disease,uncontrolled heart failure or New York Heart Association (NYHA) functionclass III or IV, awaiting cardiac transplantation or other cardiacsurgery within the next 12 months, unstable angina, acute illness oractive systemic infection or sepsis, diagnosed atrial myxoma or presenceof an interatrial baffle or patch, and the presence of implantedpacemaker or implantable cardioverter defibrillator (ICD). Further riskfactors include significant pulmonary disease or any other disease ormalfunction of the lungs or respiratory system that produces chronicsymptoms, significant congenital anomaly, women who are pregnant,enrollment in an investigational study evaluating another device,biologic, or drug, known pulmonary vein stenosis, presence of intramuralthrombus, tumor or other abnormality that precludes vascular access, ormanipulation of the catheter, presence of an inferior vena cava filter,presence of a condition that precludes vascular access, life expectancyor other disease processes likely to limit survival to less than 12months, presenting contra-indication for the devices, and patient onamiodarone at any time during the past 3 months prior to enrollment.

In some examples, the method or use includes targeting an activatedclotting time of 350-400 seconds prior to inserting the catheter andthroughout the procedure.

In some examples, the method or use includes checking an activatedclotting time levels every 15-30 minutes during the procedure to ensurean activated clotting time target of 350-400 seconds.

In some examples, the method or use includes administering a transseptalpuncture, confirming an activated clotting time target of ≥350 sec.prior to inserting the multi-electrode radiofrequency balloon catheterinto the left atrium and maintaining throughout the procedure,introducing the multi-electrode radiofrequency balloon catheter,introducing of a multi-electrode circular diagnostic catheter, ablatingthe pulmonary vein with the multi-electrode radiofrequency ballooncatheter, determining in real time pulmonary vein isolation with themulti-electrode circular diagnostic catheter, and confirming whether anentrance is blocked in the pulmonary vein.

In some examples, a method or use is disclosed for pulmonary veinisolation by applying energy to tissue of a subject's heart proximate toan esophagus, phrenic nerve, or lung. The method or use includesachieving a predetermined effectiveness rate according to any of theabove by positioning an expandable member proximate to the left atrium,the expandable member having a longitudinal axis and including aplurality of electrodes disposed about the longitudinal axis, eachelectrode capable of being energized independently, the plurality ofelectrodes including a first electrode having a first radiopaque markerand a second electrode having a second radiopaque marker different fromthe first radiopaque marker, viewing an image of the expandable memberas well as the first and second radiopaque markers in the left atrium,determining an orientation of the first and second radiopaque markerswith respect to a portion of the left atrium closest to the esophagus,phrenic nerve, or lung, of the subject, moving one of the first andsecond radiopaque markers to a portion of the left atrium closest to theesophagus, phrenic nerve or lung, and energizing one or more electrodesindexed to the one of the radiopaque markers proximate the portion closeto the esophagus, phrenic nerve, or lung, at a lower energizationsetting as compared to other electrodes to create a transmural lesion inthe left atrium with little or no effect to adjacent anatomicalstructures.

In some examples, use of an independently controlled multi-electroderadiofrequency balloon catheter is disclosed to treat paroxysmal atrialfibrillation, comprising delivering a multi-electrode radiofrequencyballoon catheter having a plurality of independently controllableelectrodes for radiofrequency ablation and a multi-electrode diagnosticcatheter to one or more targeted pulmonary veins; ablating tissue of theone or more targeted pulmonary veins with one or more of the pluralityof the electrodes independently controlled multi-electroderadiofrequency balloon catheter; diagnosing the one or more targetedpulmonary veins using the multi-electrode diagnostic catheter; andachieving at least one of a predetermined clinical effectiveness andacute effectiveness of the multi-electrode radiofrequency ballooncatheter and the multi-electrode diagnostic catheter in the isolation ofthe one or more targeted pulmonary veins, during and approximately 3months after the ablating step.

In some examples, acute effectiveness is defined by confirming if thereis an entrance block in all targeted pulmonary veins after adenosineand/or isoproterenol challenge.

In some examples, the use includes determining the acute effectivenessdetermined at approximately 3 months after the ablating step; andgenerating an estimated acute effectiveness at approximately 12 monthsafter the ablating step based on the acute effectiveness determined atapproximately 3 months.

In some examples, the estimated acute effectiveness at approximately 12months is substantially similar to the acute effectiveness determined atapproximately 3 months.

In some examples, the acute effectiveness is further defined by successgreater than 90% for the plurality of patients.

In some examples, the acute effectiveness is further defined by successgreater than 95% for the plurality of patients.

In some examples, a Type-1 error rate for power the acute effectivenessand the clinical effectiveness of all targeted veins are controlled atapproximately a 5% level, the use includes determining whether theablating is clinically successful for the plurality of patients if boththe acute effectiveness and the clinical effectiveness indications arecontrolled at approximately the 5% level.

In some examples, the acute effectiveness is at least 80% for theplurality of patients being at least 80 patients.

In some examples, the acute effectiveness is at least 80% for theplurality of patients being at least 130 patients.

In some examples, the acute effectiveness is at least 80% for theplurality of patients being at least 180 patients.

In some examples, the acute effectiveness is at least 80% for theplurality of patients being at least 230 patients.

In some examples, the acute effectiveness is further defined byconfirming if there is an entrance block in all targeted pulmonary veinsafter adenosine and/or isoproterenol challenge using a focal ablationcatheter.

In some examples, the acute effectiveness is further defined byconfirming if there is an entrance block in all targeted pulmonary veinsafter adenosine and/or isoproterenol challenge without using a focalablation catheter.

In some examples, the ablating is administered on the plurality ofpatients diagnosed with symptomatic paroxysmal atrial fibrillation.

In some examples, the step of diagnosing further comprises anelectrophysiological mapping of the heart.

In some examples, the multi-electrode diagnostic catheter furthercomprises a high torque shaft with a halo-shaped tip section containinga plurality of pairs of electrodes visible under fluoroscopy.

In some examples, the predetermined acute effectiveness is defined byulceration being absent in the plurality of patients after the ablating.

In some examples, the predetermined acute effectiveness is defined by acomplication rate of approximately 13% or fewer of the plurality ofpatients experiencing esophageal erythema after the ablating.

In some examples, the predetermined acute effectiveness is defined by acomplication rate of approximately 25% or fewer of the plurality ofpatients experiencing new asymptomatic cerebral embolic lesions afterthe ablating.

In some examples, the predetermined acute effectiveness is defined by acomplication rate of approximately 20% or fewer of the plurality ofpatients experiencing new asymptomatic cerebral embolic lesions afterthe ablating.

In some examples, the predetermined acute effectiveness is defined by acomplication rate of approximately 5-9% or fewer of the plurality ofpatients experiencing a primary adverse event by approximately 7 or moredays after the ablating.

In some examples, inclusion criteria for the plurality of patientsincludes a diagnosis with symptomatic paroxysmal atrial fibrillation;and a patient capability to comply with uninterrupted per-protocolanticoagulation requirements.

In some examples, the predetermined acute effectiveness is defined by atotal procedure time.

In some examples, the predetermined acute effectiveness is defined by atotal ablation time.

In some examples, the predetermined acute effectiveness is defined by atotal RF application time.

In some examples, the predetermined acute effectiveness is defined by atotal dwell time of the multi-electrode radiofrequency balloon catheter.

In some examples, the predetermined acute effectiveness is defined by atotal time to isolate all targeted pulmonary veins.

In some examples, the predetermined acute effectiveness is defined by anumber and a total time of applications by the multi-electroderadiofrequency balloon catheter per location of all targeted pulmonaryveins.

In some examples, the predetermined acute effectiveness is defined by anumber and a total time of applications by the multi-electroderadiofrequency balloon catheter per patient.

In some examples, the predetermined acute effectiveness is defined by anumber and a total time of applications by the multi-electroderadiofrequency balloon catheter per targeted vein.

In some examples, the multi-electrode radiofrequency balloon cathetercomprises a compliant balloon with a plurality of electrodes bondedconfigured to deliver RF energy to tissue of the pulmonary vein andsense temperature at each electrode.

In some examples, clinical effectiveness is defined by an incidence ofearly onset of one or more adverse events within a predetermined time ofthe use being implemented.

In some examples, the predetermined time is at least 7 days.

In some examples, the one or more adverse events comprise: death,atrio-esophageal fistula, myocardial infarction, cardiactamponade/perforation, thromboembolism, stroke, TIA (Transient IschemicAttack), phrenic nerve paralysis, pulmonary vein stenosis, and the majorvascular access bleeding.

In some examples, the one or more adverse events comprise: incidence ofindividual adverse events from a primary composite; incidence of seriousadverse device effect; incidence of serious adverse events within 7days, at least 730 days, and at least 30 days following the ablating;incidence of non-serious adverse events; incidence of pre-andpost-ablation asymptomatic and symptomatic cerebral emboli as determinedby MRI evaluation; and frequency, anatomic location, and size (diameterand volume) of cerebral emboli by MRI evaluations at baseline,post-ablation and during follow-up.

In some examples, the one or more adverse events for approximately 5-9%of the plurality of patients, the one or more adverse events including

-   -   NIHSS (National Institute of Health Stroke Scale) scores at        baseline, post-ablation and during follow-up;    -   a summary of MoCA (Montreal Cognitive Assessment) and mRS        (Modified Ranking Scale) scores at baseline, 1 month and during        further follow-up; a rate of hospitalization for cardiovascular        events; a percentage (%) of pulmonary vein isolation touch-up by        focal catheter among the one or more targeted veins;    -   a percentage (%) of subjects with use of focal catheter        ablations for non-PV triggers;    -   a percentage (%) of subjects with freedom from documented        symptomatic atrial fibrillation (AF), atrial tachycardia (AT),        or atypical (left side) atrial flutter (AFL) episodes        (episodes >30 seconds on arrhythmia monitoring device from day        91 to 180);    -   a percentage (%) of subjects with freedom from documented atrial        fibrillation (AF), atrial tachycardia (AT), or atypical (left        side) atrial flutter (AFL);    -   one or more episodes that endure for 30 or more seconds on an        arrhythmia monitoring device from day 91 to 180 following the        ablating; and    -   one or more procedural parameters including total procedure and        ablation time, balloon dwell time, RF application time, a number        of RF applications, fluoroscopy time and dose.

In some examples, wherein the acute safety rate includes complicationrates of 10% or less and is defined by incidence of asymptomaticcerebral embolic lesions at a discharge magnetic resonance imaging(MRI).

In some examples, the acute effectiveness rate is 100% and is defined byelectrically isolating all targeted pulmonary veins without use of afocal ablation catheter.

In some examples, the acute effectiveness rate is defined by a freedomfrom documented atrial fibrillation, atrial tachycardia, or atypicalatrial flutter episodes based on electrocardiographic data through aneffectiveness evaluation period (1 year).

In some examples, the acute effectiveness rate is defined by pulmonaryvein isolation touch-up by a focal catheter among all targeted pulmonaryveins.

In some examples, the predetermined clinical effectiveness rate isdefined by 10% or less complication rates related to incidence ofpost-ablation symptomatic and asymptomatic cerebral emboli as comparedto pre-ablation.

In some examples, the multi-electrode diagnostic catheter is configuredfor electrophysiological recording and stimulation of the atrial regionof the heart and is used in conjunction with the multi-electroderadiofrequency balloon catheter.

In some examples, use of an independently controlled multi-electroderadiofrequency balloon catheter is disclosed to treat a plurality ofpatients for paroxysmal atrial fibrillation, including delivering amulti-electrode radiofrequency balloon catheter having a plurality ofindependently controllable electrodes for radiofrequency ablation and amulti-electrode diagnostic catheter to one or more targeted pulmonaryveins; and ablating tissue of one or more targeted pulmonary veins withone or more of the plurality of the electrodes independently controlledmulti-electrode radiofrequency balloon catheter; diagnosing all targetedpulmonary veins using the multi-electrode diagnostic catheter; andachieving a predetermined rate of adverse events based on use of themulti-electrode radiofrequency balloon catheter and the multi-electrodediagnostic catheter in the isolation of all targeted pulmonary veins,during and approximately 6 months after use.

In some examples, use of an independently controlled multi-electroderadiofrequency balloon catheter is disclosed to treat a plurality ofpatients for paroxysmal atrial fibrillation, including evaluating anumber and size of all targeted pulmonary veins and anatomy of the leftatrial; puncturing the transseptal; selectively positioning amulti-electrode esophageal temperature monitoring device in thevasculature with respect to all targeted pulmonary veins; selectivelypositioning a multi-electrode radiofrequency balloon catheter in thevasculature with respect to all targeted pulmonary veins, themulti-electrode radiofrequency balloon catheter having a plurality ofindependently controllable electrodes for radiofrequency ablation;selectively positioning a multi-electrode diagnostic catheter in thevasculature with respect to all targeted pulmonary veins; ablatingtissue of all targeted pulmonary veins with one or more of the pluralityof the electrodes independently controlled multi-electroderadiofrequency balloon catheter; confirming isolation of all targetedpulmonary veins using the multi-electrode diagnostic catheter;confirming existence of an entrance block in all targeted pulmonaryveins; achieving a predetermined clinical effectiveness and/or acuteeffectiveness of the method or use, based on the confirmed existence ofthe entrance block, regarding the isolation of all targeted pulmonaryveins following the method or use.

In some examples, use includes mapping all targeted pulmonary veinsusing the diagnostic catheter.

In some examples, exclusion criteria for the plurality of patientscomprises at least one of the following:

-   -   atrial fibrillation secondary to electrolyte imbalance, thyroid        disease, or reversible or non-cardiac cause;    -   previous surgical or catheter ablation for atrial fibrillation;    -   anticipated to receive ablation outside all targeted pulmonary        veins ostia and CTI region;    -   previously diagnosed with persistent, longstanding atrial        fibrillation and/or continuous atrial fibrillation >7 days,        or >48 hrs terminated by cardioversion;    -   any percutaneous coronary intervention (PCI) within the past 2        months;    -   valve repair or replacement and presence of a prosthetic valve;    -   any carotid stenting or endarterectomy;    -   coronary artery bypass grafting, cardiac surgery, valvular        cardiac surgical or percutaneous procedure within the past 6        months;    -   documented left atrium thrombus on baseline imaging;    -   LA antero posterior diameter greater than 50 mm;    -   any pulmonary vein with a diameter greater than or equal to 26        mm;    -   left ventricular ejection fraction less than 40%;    -   contraindication to anticoagulation;    -   history of blood clotting or bleeding abnormalities;    -   myocardial infarction within the past 2 months;    -   documented thromboembolic event within the past 12 months;    -   rheumatic heart disease;    -   awaiting cardiac transplantation or other cardiac surgery within        the next 12 months;    -   unstable angina;    -   acute illness or active systemic infection or sepsis;    -   diagnosed atrial myxoma or interatrial baffle or patch;    -   presence of implanted pacemaker, implantable cardioverter        defibrillator, tissue-embedded, or iron-containing metal        fragments;    -   significant pulmonary disease or any other disease or        malfunction of the lungs or respiratory system that produces        chronic symptoms;    -   significant congenital anomaly;    -   pregnancy or lactating;    -   enrollment in an investigational study evaluating another        device, biologic, or drug;    -   pulmonary vein stenosis;    -   presence of intramural thrombus, tumor or other abnormality that        precludes vascular access, or manipulation of the catheter;    -   presence of an IVC filter;    -   presence of a condition that precludes vascular access;    -   life expectancy or other disease processes likely to limit        survival to less than 12 months;    -   contraindication to use of contrast agents for MRI;    -   presence of iron-containing metal fragments in the patient; or    -   unresolved pre-existing neurological deficit.

In some examples, the multi-electrode radiofrequency balloon catheterincludes a compliant balloon with a plurality of electrodes configuredto deliver RF energy to tissue of all targeted pulmonary veins and sensetemperature at each electrode.

In some examples, the plurality of electrodes is oriented circularly tocircumferentially contact with an ostia of the pulmonary vein.

In some examples, the use includes using the plurality of electrodes forvisualization, stimulation, recording, and ablation.

In some examples, each electrode is configured so an amount of powerdelivered to each electrode is controlled independently.

In some examples, the multi-electrode radiofrequency balloon catheterfurther includes a proximal handle, a distal tip, and a middle sectiondisposed therebetween.

In some examples, the proximal handle is a deflection thumb knoballowing for unidirectional deflection, a balloon advancement mechanism,and a luer fitting for balloon inflation and irrigation.

In some examples, the multi-electrode radiofrequency balloon catheterincludes a high-torque shaft configured to be rotated to facilitateaccurate positioning of the catheter tip to a desired; and aunidirectional braided deflectable tip section.

In some examples, use includes controlling irrigation to themulti-electrode radiofrequency balloon catheter with an irrigation pump.

In some examples, use includes administering uninterruptedanticoagulation therapy at least 1 month prior to the procedure.

In some examples, if the patient is receiving warfarin/coumadin therapy,the patient must have an international normalized ratio (INR) ≥2 for atleast 3 weeks prior to the procedure.

In some examples, if the patient is receiving warfarin/coumadin therapy,the patient must be confirmed to have an international normalized ratio(INR) ≥2 within 48 hours pre-procedure.

In some examples, use includes continuing anticoagulation therapy priorto the procedure.

In some examples, use includes administering a transseptal puncture;confirming an activated clotting time target of ≥350 sec. prior toinserting the multi-electrode radiofrequency balloon catheter into theleft atrium and maintaining throughout the procedure; introducing themulti-electrode radiofrequency balloon catheter; introducing of amulti-electrode circular diagnostic catheter; ablating the pulmonaryvein with the multi-electrode radiofrequency balloon catheter;determining in real time pulmonary vein isolation with themulti-electrode circular diagnostic catheter; and confirming whether anentrance is blocked in the pulmonary vein.

In some examples, wherein the multi-electrode circular diagnosticcatheter includes an elongated body having a longitudinal axis; a distalassembly distal the elongated body, the distal assembly having a helicalform comprising a proximal loop and a distal loop, and a shape-memorysupport member extending through at least the proximal loop, theproximal loop and the distal loop being oriented obliquely at an anglerelative to the longitudinal axis of the elongated body; at least oneirrigated ablation ring electrode mounted on the proximal loop; acontrol handle proximal the elongated body; and a contraction wirehaving a proximal end in the control handle and a distal end anchored inthe proximal loop, the control handle including a first control memberconfigured to actuate the contraction wire to contract the proximalloop, wherein the proximal loop has a first flexibility and the distalloop has a second flexibility, and the second flexibility is greaterthan the first flexibility.

In some examples, use of an independently controlled multi-electroderadiofrequency balloon catheter is disclosed to treat a plurality ofpatients for paroxysmal atrial fibrillation by applying energy to tissueof a subject's heart proximate to an esophagus, phrenic nerve, or lung,including achieving at least one of a predetermined clinicaleffectiveness and acute effectiveness of the procedure based on use ofthe multi-electrode radiofrequency balloon catheter and amulti-electrode diagnostic catheter in the isolation of the one or moretargeted pulmonary veins by positioning an expandable member proximateto the left atrium, the expandable member of the multi-electroderadiofrequency balloon catheter having a longitudinal axis and includinga plurality of electrodes disposed about the longitudinal axis, eachelectrode capable of being energized independently, the plurality ofelectrodes including a first electrode having a first radiopaque markerand a second electrode having a second radiopaque marker different fromthe first radiopaque marker; viewing an image of the expandable memberas well as the first and second radiopaque markers in the left atrium;determining an orientation of the first and second radiopaque markerswith respect to a portion of the left atrium closest to the esophagus,phrenic nerve, or lung, of the subject; moving one of the first andsecond radiopaque markers to a portion of the left atrium closest to theesophagus, phrenic nerve or lung; energizing one or more electrodesindexed to the one of the radiopaque markers proximate the portion closeto the esophagus, phrenic nerve, or lung, at a lower energizationsetting as compared to other electrodes to create a transmural lesion inthe left atrium with little or no effect to adjacent anatomicalstructures; and electrophysiologically recording and stimulating theatrial region of the tissue proximate to the esophagus, phrenic nerve,or lung using the multi-electrode diagnostic catheter,

In some examples, use of an independently controlled multi-electroderadiofrequency balloon catheter is disclosed for a procedure for atrialfibrillation, including delivering a multi-electrode radiofrequencyballoon catheter to one or more targeted pulmonary veins; ablatingtissue of the pulmonary vein using the multi-electrode radiofrequencyballoon catheter; and achieving a predetermined effectiveness rate ofpulmonary vein isolation.

In some examples, the predetermined effectiveness rate includescomplication rates of 10% or less and is defined by existence ofasymptomatic cerebral embolic lesions at a discharge magnetic resonanceimaging (MRI).

In some examples, the predetermined effectiveness rate is defined by afreedom from documented atrial fibrillation, atrial tachycardia, oratypical atrial flutter episodes based on electrocardiographic datathrough an effectiveness evaluation period.

In some examples, the effectiveness evaluation period is approximatelyone year.

In some examples, the predetermined effectiveness rate is defined bypulmonary vein isolation touch-up by a focal catheter among all targetedpulmonary veins.

In some examples, the predetermined effectiveness rate is defined byusing focal catheter ablation for non-PV triggers during the indexprocedure.

In some examples, the predetermined effectiveness rate comprises a longterm effectiveness rate.

In some examples, the predetermined effectiveness rate is defined by anaverage number of RF applications per patient and RF time required toisolate all pulmonary veins.

In some examples, the predetermined effectiveness rate is defined by anaverage number of RF applications per vein and RF time required toisolate common pulmonary veins.

In some examples, the predetermined effectiveness rate is defined by anaverage number of RF applications per patient and RF time required toisolate common pulmonary veins.

In some examples, the predetermined effectiveness rate is defined bydetermining incidence of complication rates being 10% or less ofpost-ablation symptomatic and asymptomatic cerebral emboli as comparedto pre-ablation.

In some examples, the predetermined effectiveness rate is defined byevaluating a presence of emboli-associated neurological deficits by atleast one of NIHSS and mRS assessments.

In some examples, the multi-electrode radiofrequency balloon catheter isconfigured for use in catheter-based cardiac electrophysiologicalmapping of the atria.

In some examples, the multi-electrode radiofrequency balloon catheter isconfigured for cardiac ablation.

In some examples, the multi-electrode radiofrequency balloon cathetercomprises:

a compliant balloon with a plurality of electrodes bonded configured todeliver RF energy to tissue of the pulmonary vein and sense temperatureat each electrode.

In some examples, the plurality of electrodes is oriented circularly tocircumferentially contact with an ostia of the pulmonary vein.

In some examples, the use includes using the plurality of electrodes forvisualization, stimulation, recording, and ablation.

In some examples, each electrode is configured so an amount of powerdelivered to each electrode is controlled independently.

In some examples, the multi-electrode radiofrequency balloon catheterfurther includes a proximal handle, a distal tip, and a middle sectiondisposed therebetween.

In some examples, the proximal handle is a deflection thumb knoballowing for unidirectional deflection, a balloon advancement mechanism,and a luer fitting for balloon inflation and irrigation.

In some examples, the multi-electrode radiofrequency balloon catheterfurther includes a high-torque shaft configured to be rotated tofacilitate accurate positioning of the catheter tip to a desired; and aunidirectional braided deflectable tip section.

In some examples, the balloon has a membrane, the balloon having adistal end and a proximal end defining a longitudinal axis, themulti-electrode radiofrequency balloon catheter further includes a firstsubstrate disposed on the membrane, the first substrate including afirst radiopaque marker of a first form disposed thereon; and a secondsubstrate disposed on the membrane, the second substrate including asecond radiopaque marker of a second form disposed thereon, the secondform being different from the first form.

In some examples, use includes controlling irrigation to themulti-electrode radiofrequency balloon catheter with an irrigation pump.

In some examples, the effectiveness evaluation period is at least 91days following the delivering the multi-electrode radiofrequency ballooncatheter to the pulmonary vein; and the ablating tissue of the pulmonaryvein using the multi-electrode radiofrequency balloon catheter.

In some examples, the effectiveness evaluation period is less than orequal to one year following the delivering the multi-electroderadiofrequency balloon catheter to the pulmonary vein; and the ablatingtissue of the pulmonary vein using the multi-electrode radiofrequencyballoon catheter.

In some examples, use of administering an independently controlledmulti-electrode radiofrequency balloon catheter for a procedure foratrial fibrillation is disclosed, including delivering a multi-electroderadiofrequency balloon catheter to a pulmonary vein; ablating tissue ofthe pulmonary vein using the multi-electrode radiofrequency ballooncatheter; and achieving a predetermined success rate of pulmonary veinisolation.

In some examples, the predetermined success rate is 60% for a populationsize of at least 40 patients.

In some examples, a population size for the predetermined success rateis at least 300 patients.

In some examples, a population size for the predetermined success rateis at least 200 patients.

In some examples, a population size for the predetermined success rateis at least 100 patients.

In some examples, a population size for the predetermined success rateis at least 50 patients.

In some examples, the predetermined success rate is at least 60%.

In some examples, the predetermined success rate is determined byevaluating the patient 7 days following the delivering themulti-electrode radiofrequency balloon catheter to the pulmonary vein;and the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

In some examples, the predetermined success rate is determined byevaluating the patient 1 month following the delivering themulti-electrode radiofrequency balloon catheter to the pulmonary vein;and the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

In some examples, the predetermined success rate is determined byevaluating the patient 6 months following the delivering themulti-electrode radiofrequency balloon catheter to the pulmonary vein;and the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

In some examples, the predetermined success rate is determined byevaluating the patient 12 months following the delivering themulti-electrode radiofrequency balloon catheter to the pulmonary vein;and the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

In some examples, the predetermined success rate further includesconfirming an entrance block in the pulmonary vein after at least one ofadenosine and isoproterenol challenge.

In some examples, the delivering step further comprises using a focalcatheter.

In some examples, the patient suffering at least one of the followingevents is deemed as unsuccessful pulmonary vein isolation, including:

-   -   device or procedure related death;    -   atrio-esophageal fistula, myocardial infarction;    -   cardiac Tamponade/Perforation;    -   thromboembolism;    -   stroke/Cerebrovascular Accident (CVA);    -   transient Ischemic Attach (TIA);    -   phrenic Nerve Paralysis, Pulmonary Vein Stenosis;    -   pericarditis;    -   pulmonary Edema;    -   major Vascular Access Complication/Bleeding; and    -   hospitalization (initial or prolonged).

In some examples, the patient suffering at least one of the followingevents is deemed as unsuccessful pulmonary vein isolation, including

-   -   acute procedural failure;    -   repeat ablation or surgical treatment for AF/AT/Atypical        (left-side) AFL after the blanking period (after day 90 post        index procedure);    -   DC cardioversion for AF/AT/Atypical (left-side) AFL, continuous        AF/AT/AFL on a standard 12-lead ECG even if the recording is        less than 30 seconds in duration (after day 90 post index        procedure);    -   a new Class I and/or Class III AAD is prescribed for AF during        effectiveness evaluation period (day 91-365 post index        procedure) or prescribed during the blanking period and        continued past 90 days;    -   a previously failed Class I and/or Class III AAD (failed at or        before screening) is taken for AF at a greater dose than the        highest ineffective historical dose during the effectiveness        evaluation period; and    -   amiodarone is prescribed post procedure.

In some examples, use of administering an independently controlledmulti-electrode radiofrequency balloon catheter for a procedure forcardiac electrophysiological ablation of pulmonary veins of the atriaand treating drug refractory recurrent symptomatic pulmonary atrialfibrillation, including delivering a multi-electrode radiofrequencyballoon catheter to a pulmonary vein; ablating tissue of the pulmonaryvein using the multi-electrode radiofrequency balloon catheter; andachieving a predetermined effectiveness rate of pulmonary veinisolation.

In some examples, use of administering an independently controlledmulti-electrode radiofrequency balloon catheter is disclosed for cardiacelectrophysiological ablation of pulmonary veins of the atria and drugrefractory recurrent symptomatic pulmonary atrial fibrillation,including, including delivering a multi-electrode radiofrequency ballooncatheter to a pulmonary vein; ablating tissue of the pulmonary veinusing the multi-electrode radiofrequency balloon catheter; and achievingpulmonary vein isolation and at least a 97% safety endpoint within seven(7) days of successful pulmonary vein isolation.

In some examples, use of administering an independently controlledmulti-electrode radiofrequency balloon catheter is disclosed for drugrefractory recurrent symptomatic pulmonary atrial fibrillation,including delivering a multi-electrode radiofrequency balloon catheterto a pulmonary vein; ablating tissue of the pulmonary vein using themulti-electrode radiofrequency balloon catheter; and achieving pulmonaryvein isolation and at least a 90% safety endpoint within seven (7) daysof successful pulmonary vein isolation.

In some examples, the safety endpoint is defined by a patient sufferinga primary adverse event.

In some examples, the use includes administering uninterruptedanticoagulation therapy at least 1 month prior to the procedure.

In some examples, if the patient is receiving warfarin/coumadin therapy,the patient must have an international normalized ratio ≥2 for at least3 weeks prior to the procedure.

In some examples, if the patient is receiving warfarin/coumadin therapy,the patient must be confirmed to be ≥2 within 48 hours pre-procedure.

In some examples, the use includes continuing anticoagulation therapyprior to the procedure.

In some examples, the use includes targeting an activated clotting timeof 350-400 seconds prior to inserting the catheter and throughout theprocedure.

In some examples, the use includes checking an activated clotting timelevels every 15-30 minutes during the procedure to ensure an activatedclotting time target of 350-400 seconds.

In some examples, the use includes administering a transseptal puncture;confirming an activated clotting time target of ≥350 sec. prior toinserting the multi-electrode radiofrequency balloon catheter into theleft atrium and maintaining throughout the procedure; introducing themulti-electrode radiofrequency balloon catheter; introducing of amulti-electrode circular diagnostic catheter; ablating the pulmonaryvein with the multi-electrode radiofrequency balloon catheter;determining in real time pulmonary vein isolation with themulti-electrode circular diagnostic catheter; and confirming whether anentrance is blocked in the pulmonary vein.

In some examples, the multi-electrode circular diagnostic catheterincludes an elongated body having a longitudinal axis; a distal assemblydistal the elongated body, the distal assembly having a helical formcomprising a proximal loop and a distal loop, and a shape-memory supportmember extending through at least the proximal loop, the proximal loopand the distal loop being oriented obliquely at an angle relative to thelongitudinal axis of the elongated body; at least one irrigated ablationring electrode mounted on the proximal loop; a control handle proximalthe elongated body; and a contraction wire having a proximal end in thecontrol handle and a distal end anchored in the proximal loop, thecontrol handle including a first control member configured to actuatethe contraction wire to contract the proximal loop, wherein the proximalloop has a first flexibility and the distal loop has a secondflexibility, and the second flexibility is greater than the firstflexibility.

In some examples, use of administering an independently controlledmulti-electrode radiofrequency balloon catheter is disclosed for aprocedure for pulmonary vein isolation by applying energy to tissue of asubject's heart proximate to an esophagus, phrenic nerve, or lung,including achieving a predetermined effectiveness rate according to anyof the previous claims by positioning an expandable member proximate tothe left atrium, the expandable member having a longitudinal axis andincluding a plurality of electrodes disposed about the longitudinalaxis, each electrode capable of being energized independently, theplurality of electrodes including a first electrode having a firstradiopaque marker and a second electrode having a second radiopaquemarker different from the first radiopaque marker; viewing an image ofthe expandable member as well as the first and second radiopaque markersin the left atrium; determining an orientation of the first and secondradiopaque markers with respect to a portion of the left atrium closestto the esophagus, phrenic nerve, or lung, of the subject; moving one ofthe first and second radiopaque markers to a portion of the left atriumclosest to the esophagus, phrenic nerve or lung; and energizing one ormore electrodes indexed to the one of the radiopaque markers proximatethe portion close to the esophagus, phrenic nerve, or lung, at a lowerenergization setting as compared to other electrodes to create atransmural lesion in the left atrium with little or no effect toadjacent anatomical structures.

To the accomplishment of the foregoing and related ends, certainillustrative aspects are described herein in connection with thefollowing description and the appended drawings. These aspects areindicative, however, of but a few of the various ways in which theprinciples of the claimed subject matter can be employed and the claimedsubject matter is intended to include all such aspects and theirequivalents. Other advantages and novel features can become apparentfrom the following detailed description when considered in conjunctionwith the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and further aspects of this invention are further discussedwith reference to the following description in conjunction with theaccompanying drawings, in which like numerals indicate like structuralelements and features in various figures. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingprinciples of the invention. The figures depict one or moreimplementations of the inventive devices, by way of example only, not byway of limitation.

FIG. 1 is a schematic illustration of a medical procedure using exampleinstrumentation of this disclosure.

FIG. 2 is a top view of one example catheter of this disclosure with aballoon in an expanded state, in use with a lasso catheter.

FIG. 3 is a perspective view of a balloon along with the lasso catheter.

FIG. 4A is an exploded perspective view of the medical probe which showsa base balloon or first expandable membrane with radiating electrodeassemblies that are partially covered by respective second and thirdexpandable membranes;

FIG. 4B illustrates an assembled medical probe of FIG. 3 ;

FIG. 5 is a side view of the medical probe of FIG. 3 ;

FIG. 6A is a blown-up side view of a portion of the membrane of FIG. 4A;

FIG. 6B illustrates a lateral or circumferential surface area (shadedportion) not covered by the hemispherical second and third expandablemembranes of FIG. 3 .

FIG. 7 is a photograph of an actual prototype according to an embodimentdescribed and illustrated herein.

FIG. 8 is a photograph of yet another prototype of the embodimentsdescribed and illustrated herein.

FIG. 9 is a side view of a distal end of the catheter of FIG. 2 deployedin the region of a pulmonary vein and its ostium.

FIG. 10 is a top plan view of an example diagnostic catheter of thepresent disclosure.

FIG. 11 is a detailed view of a distal assembly of the diagnosticcatheter of FIG. 5 .

FIG. 12 is a schematic sectional view of a heart showing insertion of adiagnostic catheter according to FIGS. 10 and 11 and into the leftatrium.

FIG. 13 shows a schematic overview of the study of this disclosure.

FIG. 14 shows a table summarizing recommended RF Energy DeliveryParameters in one example.

FIG. 15 shows a table summarizing intensity or severity of each AEassessed according to classifications.

FIG. 16 shows a table illustrating classifications based on AAD therapyadministered in the blanking and post-blanking periods in an examplestudy.

FIG. 17 shows example information from the study of this disclosure.

FIG. 18 shows a table summarizing results from the first study of thisdisclosure compared with a prior study.

FIG. 19A shows a graph summarizing silent cerebral lesions by visit fromthe first study of this disclosure compared with a prior study.

FIG. 19B shows a graph summarizing mean activated clotting time inpatients with and without silent cerebral lesion from the first study ofthis disclosure compared with a prior study.

FIG. 20 depicts a graphical overview of one method or use according tothis disclosure.

FIG. 21 depicts a graphical overview of one method or use according tothis disclosure.

FIG. 22 depicts a graphical overview of one method or use according tothis disclosure.

FIG. 23 depicts a graphical overview of one method or use according tothis disclosure.

FIG. 24 depicts a graphical overview of one method or use according tothis disclosure.

FIG. 25 depicts a graphical overview of one method or use according tothis disclosure.

FIG. 26 depicts a graphical overview of one method or use according tothis disclosure.

FIG. 27 depicts a graphical overview of one method or use according tothis disclosure.

DETAILED DESCRIPTION

Although example embodiments of the disclosed technology are explainedin detail herein, it is to be understood that other embodiments arecontemplated. Accordingly, it is not intended that the disclosedtechnology be limited in its scope to the details of construction andarrangement of components set forth in the following description orillustrated in the drawings. The disclosed technology is capable ofother embodiments and of being practiced or carried out in various ways.

It must also be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. By “comprising”or “containing” or “including” it is meant that at least the namedcompound, element, particle, or method or use step is present in thecomposition or article or method or use, but does not exclude thepresence of other compounds, materials, particles, method or use steps,even if the other such compounds, material, particles, method or usesteps have the same function as what is named.

As used herein, the terms “about” or “approximately” for any numericalvalues or ranges indicate a suitable dimensional tolerance that allowsthe part or collection of components to function for its intendedpurpose as described herein. More specifically, “about” or“approximately” can refer to the range of values ±20% of the recitedvalue, e.g. “about 90%” can refer to the range of values from 71% to99%.

In addition, as used herein, the terms “patient,” “host,” “user,” and“subject” refer to any human or animal subject and are not intended tolimit the systems or method or uses to human use, although use of thesubject invention in a human patient represents a preferred embodiment.

In describing example embodiments, terminology will be resorted to forthe sake of clarity. It is intended that each term contemplates itsbroadest meaning as understood by those skilled in the art and includesall technical equivalents that operate in a similar manner to accomplisha similar purpose. It is also to be understood that the mention of oneor more steps of a method or use does not preclude the presence ofadditional method or use steps or intervening method or use stepsbetween those steps expressly identified. Steps of a method or use canbe performed in a different order than those described herein withoutdeparting from the scope of the disclosed technology. Similarly, it isalso to be understood that the mention of one or more components in adevice or system does not preclude the presence of additional componentsor intervening components between those components expressly identified.

As discussed herein, vasculature of a “subject” or “patient” can bevasculature of a human or any animal. It should be appreciated that ananimal can be a variety of any applicable type, including, but notlimited thereto, mammal, veterinarian animal, livestock animal or pettype animal, etc. As an example, the animal can be a laboratory animalspecifically selected to have certain characteristics similar to a human(e.g., rat, dog, pig, monkey, or the like). It should be appreciatedthat the subject can be any applicable human patient, for example.

As discussed herein, “operator” can include a doctor, surgeon, or anyother individual or delivery instrumentation associated with delivery ofa multi-electrode RF balloon catheter for the treatment of drugrefractory atrial fibrillation to a subject.

As discussed herein, “NIHSS Score” means The National Institutes ofHealth Stroke Scale, or NIH Stroke Scale (NIHSS) and is a tool used byhealthcare providers to objectively quantify the impairment caused by astroke. The NIHSS is composed of 11 items, each of which scores aspecific ability between a 0 and 4. For each item, a score of 0typically indicates normal function in that specific ability, while ahigher score is indicative of some level of impairment. The individualscores from each item are summed in order to calculate a patient's totalNIHSS score. The maximum possible score is 42, with the minimum scorebeing a 0.

As discussed herein, “mRS” means the modified Rankin Scale (mRS) that isa commonly used scale for measuring the degree of disability ordependence in the daily activities of people who have suffered a strokeor other causes of neurological disability. The mRS scale runs from 0-6,running from perfect health without symptoms to death. An mRS score of 0is understood as no symptoms being observed. An mRS score of 1 isunderstood as no significant disability is observed and the patient isable to carry out all usual activities, despite some symptoms. An mRSscore of 2 is understood as slight disability and the patient is able tolook after own affairs without assistance, but unable to carry out allprevious activities. An mRS score of 3 is understood as moderatedisability whereby the patient can require some help but is able to walkunassisted. An mRS score of 4 is understood as moderate severedisability and the patient is unable to attend to own bodily needswithout assistance or walk unassisted. An mRS score of 5 is understoodas severe disability and the patient requires constant nursing care andattention, bedridden, incontinent. An mRS score of 6 is understood asthe patient being deceased.

As discussed herein, the term “safety”, as it relates to devices used inablating cardiac tissue, related delivery systems, or method or use oftreatment refers to a relatively low severity of adverse events,including adverse bleeding events, infusion or hypersensitivityreactions. Adverse bleeding events can be the primary safety endpointand include, for example, major bleeding, minor bleeding, and theindividual components of the composite endpoint of any bleeding event.

As discussed herein, unless otherwise noted, the term “clinicallyeffective” (used independently or to modify the term “effective”) canmean that it has been proven by a clinical trial wherein the clinicaltrial has met the approval standards of U.S. Food and DrugAdministration, EMEA or a corresponding national regulatory agency. Forexample, a clinical study can be an adequately sized, randomized,double-blinded controlled study used to clinically prove the effects ofthe cardiac ablation device(s) and related system(s) of this disclosure.Most preferably to clinically prove the effects of the device(s) withrespect to all targeted pulmonary veins, for example, to achieve aclinically effective outcome in for the patient (e.g., mRS less than orequal to 2) and/or achieve pulmonary vein isolation in those afflictedveins.

As discussed herein, the term “computed tomography” or CT means one ormore scans that make use of computer-processed combinations of manyX-ray measurements taken from different angles to producecross-sectional (tomographic) images (virtual “slices”) of specificareas of a scanned object, allowing the user to see inside the objectwithout cutting. Such CT scans of this disclosure can refer to X-ray CTas well as many other types of CT, such as positron emission tomography(PET) and single-photon emission computed tomography (SPECT).

The present disclosure is related to systems, method or uses and devicesfor ablating cardiac tissue to treat cardiac arrhythmias. Ablativeenergies are typically provided to cardiac tissue by a tip portion whichcan deliver ablative energy alongside the tissue to be ablated. Some ofthese catheters administer ablative energy from various electrodesthree-dimensional structures. Ablative procedures incorporating suchcatheters can be visualized using fluoroscopy.

Ablation of cardiac tissue to correct a malfunctioning heart is awell-known procedure. Typically, to successfully ablate, cardiacelectropotentials need to be measured at various locations of themyocardium. In addition, temperature measurements during ablationprovide data enabling the efficacy of the ablation to be measured.Typically, for an ablation procedure, the electropotentials and thetemperatures are measured before, during, and after the actual ablation.

Previous solutions have used two or more separate instructions (e.g.,one for the electropotentials and temperature measurements, and anotherfor the ablation), embodiments disclosed herein facilitate the twomeasurements, and in addition enable ablation using radiofrequencyelectromagnetic energy, using a single catheter. The catheter has alumen, and a balloon is deployed through the catheter lumen (the balloontravels through the lumen in a collapsed, uninflated configuration, andthe balloon is inflated on exiting the lumen). The balloon has anexterior wall or membrane and has a distal end and a proximal end whichdefine a longitudinal axis that extends the lumen.

As an example, FIG. 1 depicts example instrumentations that include anapparatus 12, according to an example embodiment. The procedure isperformed by an operator 14, and the procedure in the descriptionhereinbelow is assumed to comprise ablation of a portion of a myocardium16 of the heart of a human patient 18. However, it is understood thatembodiments disclosed herein are not merely applicable to this specificprocedure and can include substantially any procedure on biologicaltissue or on non-biological materials.

To perform the ablation, the operator 14 inserts a probe 20 into asheath 21 that has been pre-positioned in a lumen of the patient. Sheath21 is positioned so that a distal end 22 of probe 20 enters the heart ofthe patient. A multi-electrode radiofrequency balloon catheter 24 (e.g.,a balloon catheter), which is described in more detail below, isdeployed through a lumen 23 of the probe 20 and exits from a distal endof the probe 20. Catheter 24 can be a multi-electrode radiofrequencyballoon catheter for cardiac electrophysiological ablation of pulmonaryveins of the atria and, when used with a multi-channel RF generator, forthe treatment of drug refractory recurrent symptomatic PAF, as discussedmore particularly below. Catheter 24 can be understood as includingfeatures more clearly described in Appendix 1 of priority U.S. App. No.62/754,275, which includes U.S. Pat. No. 9,907,610; U.S. Pat. Pubs.2016/0175041; 2017/0311893; 2017/0311829; 2017/0347896; 2016/0175041;2017/0311893; 2017/0311829; and 2017/0347896 and U.S. patent applicationSer. Nos. 15/476,191; 15/939,154; 15/847,661; 15/684,434; 15/689,388;15/815,394; 15/837,339; 15/857,101; 15/870,375; 15/838,962; and62/769,424, each of which are incorporated by reference in theirentirety as if set forth verbatim herein. Note that such catheters 24can be introduced through the femoral artery, wrist artery (radialaccess) or directly through the carotid artery. While both radial andcarotid access avoids the aortic arches, there are other drawbacks.However, all three approaches are considered to be known to ones ofskill in this art.

Functionally, catheter 24 seeks to achieve isolation of the pulmonaryveins in the subject's LA to eliminate symptoms of AF. The catheter 24ablates from multiple irrigated, independently-controlled electrodessimultaneously. The amount of power delivered to each electrode iscontrolled independently to improve safety and lesion quality.

One RF generator contemplated for use in this disclosure can be forcardiac ablation applications to generate RF energy for delivery to asite in the heart via compatible RF ablation catheters. The generator iscapable of independently controlling the delivery of RF energy toelectrodes simultaneously. The generator can include functions forcontrolling ablation parameters at the ablation electrodes of thecatheter. Ablation parameters, such as power, impedance, ablationduration, and temperature are recorded and can be exported at the end ofthe procedure to a USB device.

As shown in FIG. 1 , apparatus 12 is controlled by a system processor46, which is in an operating console 15 of the apparatus. Console 15comprises controls 49 which are used by professional 14 to communicatewith the processor. During the procedure, the processor 46 typicallytracks a location and an orientation of the distal end 22 of the probe20, using any method or use known in the art. For example, processor 46can use a magnetic tracking method or use, wherein magnetic transmitters25X, 25Y and 25Z external to the patient 18 generate signals in coilspositioned in the distal end of the probe 20. The CARTO® system(available from Biosense Webster, Inc. of Irvine, California) uses sucha tracking method or use.

To operate apparatus 12, the processor 46 communicates with a memory 50,which has many modules used by the processor to operate the apparatus.Thus, the memory 50 comprises a temperature module 52, an ablationmodule 54, and an electrocardiograph (ECG) module 56, the functions ofwhich are described below. The memory 50 typically comprises othermodules, such as a force module for measuring the force on the distalend 22, a tracking module for operating the tracking method or use usedby the processor 46, and an irrigation module allowing the processor tocontrol irrigation provided for the distal end 22.

While other modules are not illustrated in FIG. 1 , others are indeedcontemplated and can include hardware as well as software elements. Forexample, module 54 can include a radio-frequency generator with at leastone output or output channel, e.g., ten outputs or ten output channels.Each of the outputs can be separately and selectively activated ordeactivated by a switch. That is, each switch can be disposed betweenthe signal generator and a respective output. Thus, a generator with tenoutputs would include ten switches. These outputs can each beindividually coupled to electrodes on an ablation catheter, e.g., theten electrodes 33 on balloon 80, described in further detail below.Electrodes 33 can be irrigated, flexible gold-plated electrodes bondedthereto and used to deliver RF energy in a unipolar fashion to thetissue and sense temperature at each electrode. Electrodes 33 can beoriented circularly to achieve good circumferential contact with theostia of the pulmonary veins. The catheter 24 can ablate cardiac tissuefrom the independently-controlled electrodes simultaneously when pairedwith a Multi-Channel RF generator and the amount of power delivered toeach electrode is controlled independently.

Such an electrical connection can be achieved by establishing anelectrical path between each output and each electrode. For example,each output can be connected to a corresponding electrode by one or morewires or suitable electrical connectors. Thus, in some embodiments, anelectrical path can include at least one wire. In some embodiments, theelectrical path can further include an electrical connector and at leasta second wire. Thus, electrodes 33 can be selectively activated anddeactivated with the switches to receive radiofrequency energyseparately from each of the other electrodes.

FIG. 2 is a top view of catheter 24. Catheter 24 has a usable length ofapproximately 110 cm (though other dimensions are contemplated as neededor required). Catheter 24 can have three major sections: handle 42,shaft portion 82 and distal tip 22. The shaft 82 can measure 10.5 F witha 13.5 F maximum outer diameter around the balloon 80 when the balloonis in its fully collapsed state. The catheter 24 can have a high-torqueshaft 82, with a uni-directional braided deflectable tip section. Theshaft allows the plane of the curved tip with balloon 80 to be rotatedto facilitate accurate positioning of the catheter tip 22 to the desiredsite (ostia of the pulmonary veins). The compliance of the balloon 80allows for its flexible surface electrodes 33 to conform to the anatomywhen pressed against the tissue.

The handle section 42 can incorporate a deflection thumb knob allowingfor unidirectional deflection, a balloon advancement mechanism, and aluer fitting for balloon inflation and irrigation. An additional luerfitting can be included and located proximally to the ejector and serveas an entry port for a guidewire as well as distal irrigation and/orcontrast injection. The catheter 24 can be used with an irrigation pumpto control irrigation to the balloon. Heparinized normal saline can bedelivered through the luer fitting of the handle 42.

FIG. 3 is a schematic perspective view of an example multi-electroderadiofrequency balloon catheter 24 in an expandable configuration in theform of a balloon in its expanded configuration, according to anembodiment. In a disclosed embodiment, where the multi-electroderadiofrequency balloon catheter 24 is used to ablate an ostium 11 of alumen, such as a pulmonary vein 13, the multi-electrode radiofrequencyballoon catheter 24 is supported by a tubular shaft 70 having a proximalshaft portion 82 and a distal shaft end 88. The shaft 70 includes ahollow central tube 74, which permits a catheter to pass therethroughand past the distal shaft end 88. The catheter can be a focal linearcatheter or a lasso catheter 72, as illustrated, ., or a diagnosticcatheter. It is also intended that the catheter can have a relativelysmall diameter (e.g., ˜3 mm) through which a similarly small diametercatheter, such as a focal linear catheter or the like, could be used.The lasso catheter 72 can be inserted into the pulmonary vein toposition the multi-electrode radiofrequency balloon catheter 24correctly with respect to the ostium prior to ablation of the ostium.The distal lasso portion of the catheter 72 is typically formed ofshape-memory retentive material such as nitinol. It is understood thatthe multi-electrode radiofrequency balloon catheter 24 can also be usedwith a linear or focal catheter 99 (as shown in broken lines in FIG. 3 )in the PV or elsewhere in the heart. Any catheter used in conjunctionwith the multi-electrode radiofrequency balloon catheter 24 can havefeatures and functions, including, for example, pressure sensing,ablation, diagnostic, e.g., navigation and pacing.

The balloon 80 of the multi-electrode radiofrequency balloon catheter 24can have an exterior wall or membrane 26 of a bio-compatible material,for example, formed from a plastic such as polyethylene terephthalate(PET), polyurethane or PEBAX®. The shaft 70 and the distal shaft end 88define a longitudinal axis 78 of the balloon 80. The balloon 80 isdeployed, in a collapsed configuration, via the lumen 23 of the probe20, and can be expanded after exiting from the distal end 22. Themembrane 26 of the balloon 80 is formed with irrigation pores orapertures 27 through which the fluid (e.g., saline) can exit from theinterior of the balloon 80 to outside the balloon for cooling the tissueablation site at the ostium. It is understood that the fluid can exitthe balloon 80 with any desired flow rate or pressure, including a ratewhere the fluid is seeping out of the balloon 80.

Yet another embodiment of the catheter was utilized in the study,referenced here as probe 24′. FIG. 4A illustrates an explodedperspective view of the electrophysiology probe 24′ that includes atubular member 302 extending along a longitudinal axis L-L from a first(proximal) end 302 b to a second (or distal) end 302 a. A firstexpandable membrane 204 is attached to the tubular member 302 near thedistal end 302 b. The membrane 204 has an outer surface 204 a and aninner surface 204 b disposed about the longitudinal axis L-L. The outersurface 204 a is exposed to the ambient environment while the innersurface 204 b is exposed to the internal volume of the balloon definedby the membrane 204. The first expandable membrane 204 has a firstexpandable distal membrane portion 208 being coupled to the second end302 a of the tubular member 302 and second expandable distal membraneportion 206 spaced apart from the first expandable distal membraneportion 208 along the longitudinal axis L-L.

It is noted that first expandable membrane 204 is configured to beexpanded from a compressed shape (generally tubular configuration) to aballoon (or generally spheroidal) shaped member. A plurality ofelectrodes (210 a, 210 b, 210 c, 210 d, 210 e, 210 f, 210 g, 210 h, 210i and 210 j, which may be referred to singularly or collectively as“electrode 210”) are disposed on the outer surface 204 a of the firstexpandable membrane 204. The electrodes 210 are arranged so that theyradiate from a generally common center or centroid substrate 212 nearthe second expandable distal membrane portion 208 which is distal to thetubular member 302. The electrodes 210 a-210 j may have one or morewires, i.e., bifilar 214 a-214 j, respectively, connected to each of theplurality of electrodes 210 a-210 j via a connection junction 216 a-216j. Each of the wires 214 a-214 j (which may be singular in form “wire”or plural “wires” will be collectively referred to as “wire 214”) isconnected to the connection point at the “underside” surface of theelectrode 210. The underside surface of each electrode 210 is theelectrode surface that is not exposed to the ambient environment and istypically bonded to the outer surface 204 a of the membrane 204. As theconnection point 216 (typically a solder point) is generally at thecenter of the electrode, the wire is covered by the underside surface ofeach electrode. However, as each wire or bifilar 214 a-214 j extendstoward the tubular member 302, the electrode surface or the substrate onwhich the electrode is bonded thereto becomes smaller thereby leavingthe wire or bifilars 214 a-214 j exposed.

As can be seen in FIG. 4B, when group of wires 214 a-214 j are mountedon the membrane 204, each wire 214 is configured to extend from thetubular member 302 to the respective electrode 210 such that each wirefollows the topographic outer surface 204 a of membrane 204. Inextending the wires 214 toward the tubular member 302, the wires 214become exposed to the ambient environment (e.g., biological tissues orblood) as each wire 214 leaves the underside surface of each electrodeor the underside surface of the substrate 213 (FIG. 5 ). As each wire214 may be used to conduct or transmit electrical energy or signals, itwould be detrimental to expose the wires 214 to the ambient biologicaltissue environment. As such, we have devised a second expandablemembrane 200 that encapsulates the one or more wires (214 a-214 j)between the second expandable membrane 200 and the first expandablemembrane 204 so that the wires 214 a-214 j are constrained between thefirst and second expandable membrane (FIG. 7 ). Such configurationeliminates the exposure of the wires to the ambient environment yetstill allowing the electrodes/thermocouples to be exposed to biologicaltissues so that the electrodes and thermocouples to work for theirintended purposes. Moreover, as the wires 214 are constrained orcaptured between the first and second membranes, there is virtually nolikelihood of the wires being entangled or mis-connected to the wrongelectrode or thermocouple during assembly. In the preferred embodiment,each wire of the bifilar is coupled to a temperature sensor in the formof a thermocouple 216 disposed on or near each electrode 210.

It is noted that tubular member 302 defines a first internal passagewayin the form of a lumen 302 c, shown here as dashed lines in FIG. 5 ,that extends from the first end 302 a to the second end 302 b of tubularmember 302 so that the one or more wires are disposed in the first lumen302 c. To allow other instruments (e.g., guide wires, optical sensoretc.,) to be delivered through the balloon 204 (and outside of thedistal-most portion 209 of balloon) the tubular member 302 can beprovided with a second lumen 302 d that extends through the membraneportions 206 and 208 to allow for another instrument to pass through thesecond lumen 302 d. Additionally, the tubular member 302 can be providedwith yet another internal passageway in the form of a third lumen 302 e.Irrigation fluid can be provided in either of the second lumen 302 d orthird lumen 302 e so that the irrigation fluid flows into the internalvolume of the membrane 204, through openings or pores 220 providedthrough the membrane inner surface 204 b and outer surface 204 a tooutside of the membrane 204 to the ambient environment (e.g., biologicaltissues or organ). Each electrode may have four irrigation openingsformed on the electrode such that the electrode irrigation openings arealigned with the pores 220 of the membrane. In the preferred embodiment,lumen 302 c, lumen 302 d and 302 e are configured or extruded asconcentric passageways, in the form of a tube 302 e within tube 302 dwithin a tube 302 c with outer tubular member 302. Tubular member 302can be a suitable biocompatible polymer as is known to those skilled inthe art.

Referring to FIG. 4B, the plurality of electrodes 210 a-210 j extendfrom a substrate centroid 212 equiangularly about the longitudinal axisL-L from the first expandable distal membrane portion 208 towards thesecond expandable distal membrane portion 206 such that the secondexpandable membrane 200 encapsulates a portion of each of the electrodes(210 a-210 j) proximate the second expandable membrane portion 206. Thesecond expandable membrane 200 has a border 202 (FIG. 4A) that extendsover a proximal portion (i.e., fish-head 115) of the electrode 210 outersurface (FIG. 4B) while allowing the electrode fish-bone pattern 210 tobe exposed to the ambient environment.

That is, each of the plurality of electrodes 210 a-210 j defines afishbone pattern not covered by the second expandable membrane 200 toallow the fishbone electrodes to be exposed to the ambient environment.Each electrode (210 a-210 j) is coupled to the outer surface of thefirst expandable membrane 204 via a substrate 213 which itself isconnected to or bonded to the outer surface 204 a of the firstexpandable membrane 204. The electrode 210 a-210 j can have a portion ofits perimeter bonded directly to membrane 204. A suitable seal 211 canbe formed so that the seal 211 runs along the outer perimeter of thesubstrate 213 of each electrode (210 a-210 j). In a preferredembodiment, the seal 211 can be provided in the form of a polyurethaneseal.

Referring to FIG. 5 , a radiopaque marker 230 is defined by a proximalfish-head portion of each electrode such that there can be respectiveradiopaque markers 230 a, 230 b, 230 c, 230 d, 230 e, 230 f, 230 g, 230h, 230 i and 230 j for corresponding electrodes 210 a-210 j. To ensurethat the location of each electrode can be determined while inside abody organ with x-rays, each electrode 210 may have a radiopaque marker(230 a-230 j) with each marker having a configuration different fromother radiopaque markers on the other electrodes.

Referring back to FIG. 4A, a third expandable membrane 300 can bedisposed proximate the first expandable distal membrane portion 208 sothat the third expandable membrane 300 encircles an outer surfaceportion of the first expandable membrane 204 about the longitudinal axisL-L proximate the distal portion 209 of the membrane 204. The thirdexpandable membrane encapsulates a portion of the substrate 213 (FIG. 5) for each of the plurality of electrodes near distal portion 209 ofmembrane 204. Preferably, the third expandable membrane 300 allows forencapsulation of the substrates 213 of each electrode (210 a-210 j) asthe substrates 213 converge to centroid 212 near the distal portion 209of the membrane 204. A retaining ring 209 is disposed about the thirdexpandable membrane 300 (near distal portion 208 of membrane 204) tohold the third expandable membrane 300 as well as the substrates 213 tothe first expandable membrane 204. The third expandable membrane 300 canbe bonded to the first expandable membrane 204 thereby capturing thesubstrate 213 therebetween the two membranes (204 and 300).

Referring to FIG. 6A, a blown-up side view of a portion of the membraneof FIG. 4A is shown. FIG. 6B shows a lateral or circumferential surfacearea (shaded portion) that is not covered. In particular, the surfacearea of the membrane 204 that is exposed (i.e., not covered) by secondexpandable membrane 200 and a third expandable membrane has acircumferential surface area L delineated between a virtual slice S1(defined by the intersection of third expandable membrane 300 with firstexpandable membrane 204) orthogonal to axis L-L and virtual slice S2orthogonal to the longitudinal axis L-L whereby slice S2 is defined bythe intersection of the second expandable membrane 200 to the firstexpandable membrane 204. For clarity, it can be seen in FIG. 6B that ifthe first expandable membrane 204 approximates a sphere (when membrane204 is expanded to its service characteristic) then the circumferentialsurface area L can be determined once the parameters of the spheroidbody is known. In the preferred embodiment, shown in FIG. 7 , the firstexpandable membrane 204 includes a circumferential surface area L (FIGS.5 and 6B) of approximately 52% of a total surface area of the firstexpandable membrane 204. That is, the circumferential surface area L isthe exposed surface area (without any electrode or substrate) of firstexpandable membrane 204 or outer circumferential area of firstexpandable membrane 204 that is also not covered by the secondexpandable membrane 200 and third expandable membrane 300. Further, itis noted that each substrate 213 for each electrode 210 includes asubstrate surface area approximately 8% of the exposed outercircumferential surface area L of the first expandable membrane 204. Inthe preferred embodiments, the second expandable membrane 200 and thirdexpandable membrane 300 cover approximately half of the outer surfacearea of the first expandable membrane 204.

In the preferred embodiments, the first expandable membrane includes agenerally spheroidal member with a diameter as referenced to thelongitudinal axis L-L of about 30 millimeters and the second expandablemembrane and the third expandable membrane each includes ahemi-spherical member with the respective major diameter of eachhemispherical member being less than 30 mm. In the preferredembodiments, the total surface area of membrane 204 is about 4500squared-mm while the circumferential surface area L is about 2400squared-mm and each flexible substrate 213 is about 200 squared-mm whenthe membrane 204 is at its fully expanded (i.e., designed)configuration, shown exemplarily in FIG. 7 .

The balloon 204 of the diagnostic/therapeutic catheter has an exteriorwall or membrane 204 a of a bio-compatible material, for example, formedfrom a plastic such as polyethylene terephthalate (PET), polyurethane orPEBAX®. The tubular shaft 302 and the distal shaft end 302 a define alongitudinal axis L-L of the balloon 204. The balloon 204 is deployed,in a collapsed configuration as described in commonly-owned U.S. patentapplication Ser. No. 15/939,154 filed on Mar. 28, 2018 via the lumen 23of the probe 20 in this prior application, which is incorporated byreference herein to this present application). The membrane 204 a of theballoon 204 is formed with irrigation pores or apertures 220 (shown inFIG. 5 ) through which the fluid (e.g., saline) can exit from theinterior of the balloon 204 to outside the balloon for cooling thetissue ablation site at the ostium.

As described earlier in relation to FIG. 4B, membrane 24 supports andcarries a combined electrode and temperature sensing member which isconstructed as a multi-layer flexible circuit electrode assembly 210a-210 j. The “flex circuit electrode assembly” 210 a-210 j may have manydifferent geometric configurations than as shown here. In theillustrated embodiment, the flex circuit electrode assembly 210 a-210 jhas a plurality of radiating substrates or strips 213 a-213 j, as bestseen in FIG. 2 . The substrates 213 a-213 j are evenly distributed aboutthe distal end 209 and the balloon 204. Each substrate 213 a-213 j haswider proximal portion that gradually tapers to a narrower distalportion as referenced to the longitudinal axis.

For simplicity, the flex circuit electrode assembly 210 is describedwith respect to one of its substrate 213 as shown in FIG. 5 , althoughit is understood that following description may apply to each substrate213 of the assembly 210. The flex circuit electrode assembly 210includes a flexible and resilient sheet substrate material 213,constructed of suitable bio-compatible materials, for example,polyimide. In some embodiments, the sheet substrate material 213 has agreater heat resistance (or a higher melting temperature) compared tothat of the balloon membrane 204. In some embodiments, the substratematerial 213 is constructed of a thermoset material having adecomposition temperature that is higher than the melting temperature ofthe balloon membrane 204 by approximately 24 degrees Celsius or more.

The substrate material 213 is formed with one or more irrigation poresor apertures (not labeled) that are in alignment with the irrigationapertures 220 of the balloon member 204 so that fluid passing throughthe irrigation apertures 220 and (not labeled) can pass to the ablationsite on the ostium.

The substrate material 213 has a first or outer surface facing away fromthe balloon membrane 204, and a second or inner surface facing theballoon membrane 204. On its outer surface, the substrate material 213supports and carries the contact electrodes 210. The configuration ortrace of the contact electrode 210 may resemble a “fishbone” but itshould be noted that the invention is not limited to such configuration.In contrast to an area or “patch” ablation electrode, the fingers of thecontact electrode 210 advantageously increase the circumferential orequatorial contact surface of the contact electrode 210 with the ostiumwhile void regions between adjacent fingers advantageously allow theballoon 204 to collapse inwardly or expand radially as needed atlocations along its equator. In the illustrated embodiment, the fingershave different lengths, some being longer, others being shorter. Forexample, the plurality of fingers includes a distal finger, a proximalfinger and fingers therebetween, where each of the fingers in betweenhas a shorter adjacent finger. For example, each finger has a lengthdifferent from its distal or proximal immediately adjacent neighboringfinger(s) such that the length of each finger generally follows thetapered configuration of each substrate 213. In the illustratedembodiment, there are 22 fingers extending across (past each lateralside of) the elongated portion. In some embodiments, the contactelectrode 210 includes gold with a seed layer between the gold and themembrane 204. The seed layer may include titanium, tungsten, palladium,silver, or combinations thereof.

As shown in FIG. 8 , the flexible electrode may have its radiopaquemarker in the variation identified as 231 a, 231 b, 231 c and so on toassist in the identification of the electrode being energized. Themarkers 231 a-231 j have various serpentine configurations (as comparedto FIG. 7 ) to allow for increased flexibility due to the presence ofthe second membrane 200 which tend to reduce the flexibility of thedevice near the markers 231 a-231 j.

The membrane 26 supports and carries a combined electrode andtemperature sensing member which is constructed as a multi-layerflexible circuit electrode assembly 84. The “flex circuit electrodeassembly” 84 can have many different geometric configurations. In theillustrated embodiment, the flex circuit electrode assembly 84 has aplurality of radiating substrates or strips 30. One or more electrodes33 on each substrate come into galvanic contract with the ostium 11during an ablation procedure, during which electrical current flows fromthe electrodes 33 to the ostium 11, as shown in FIG. 9 .

The circuit which contains the electrodes 33 can be made of a veryflexible and resilient polyimide substrate (e.g., about 0.001 inchthick) with a layer of gold on the top (exterior surface) and a layer ofgold plated copper on the back side (between the circuit and the balloon80). In order to deliver current to the electrodes 33, a bifilar wirecan be connected to each electrode 33, routed through the catheter 24,and terminated in the connector in the handle 42. The bifilar wire canbe made of one copper and one constantan wire. The copper wire can beused for RF delivery. In order to fit the catheter 24 into the sheath,it is necessary to first collapse the balloon 80 with its flexibleelectrodes 33 to a smaller diameter by moving the distal end of theballoon 80 forward a specific distance to provide the elongationnecessary to decrease the balloon's outer diameter (OD).

One example of diagnostic catheter 110 used in this disclosure is shownin FIGS. 10-11 and includes lasso-type structures to facilitatemaneuvering and positioning in the heart. Catheter 110 can be understoodas including features more clearly described in Appendix 2 of U.S.62/754,275 which includes U.S. Pat. Nos. 5,718,241; 6,198,974;6,484,118; 6,987,995; 7,142,903; 7,274,957; 7,377,906; 7,591,799;7,593,760; 7,720,517; 7,853,302; 8,000,765; 8,021,327; 8,275,440; and8,348,888, each of which are incorporated by reference in their entiretyas if set forth verbatim herein. Such catheters 110 can be used toproduce curved, circular, looped or otherwise closed ablation paths, aswell as sensing electrical activity along a curve, circle, loop orclosed pattern for electrical potential and anatomical mapping.

Catheter 110 can therefore be an electrophysiological recording andstimulation of the atrial region of the heart and can be used inconjunction with catheter 24, as well as other ancillary equipment.Catheter 110's distal end can be a circular spine with ring electrodeslocated circularly and are used for stimulation and recording within theatria. The looped distal end is available in multiple diameters (15 mm,20 mm and 25 mm) to achieve an optimal contact in variably sizedpulmonary veins. In some examples, the loop tip can be a circular spinewith ten electrodes bonded to its surface, a straight distal tip sectionand a hypotube shaft. The ten electrodes can be used for stimulation andrecording within the atria of the heart and oriented circularly on theloop to achieve appropriate circumferential contact with the inside ofthe PV. Nominal electrode spacing can include 4.5 mm for the 15 mm loop,6 mm for the 20 mm loop, and 8mm for the 25 mm loop.

Catheter 110 according to the disclosed example can include an elongatedbody that can include an insertion shaft or catheter body 112 having alongitudinal axis, and an intermediate section 114 distal of thecatheter body that can be uni- or bi-directionally deflected off axisfrom the catheter body longitudinal axis. A resilient three-dimensionaldistal assembly 117, with ring electrodes 119 disposed along a nonlinearor curved distal portion, extends from the elongated body 112 or theintermediate section 114. The helical form is oriented obliquelyrelative to a longitudinal axis 125 of the catheter 110 extending fromthe intermediate section 114. The term “obliquely”, in this respectmeans that the plane P in space that best fits the helical form isangled relative to the longitudinal axis 125. An angle θ between theplane P and the axis 125 ranges between about 45 to 105 degrees,preferably between about 75 to 105 degrees, and more preferably about 90degrees. Moreover, the helical form 122 of the distal assembly 117spirals or subtends in a predetermined manner.

The distal assembly 117 can have an electrode-carrying proximal loop117P, and a soft “pigtail” that includes a distal loop 117D and a distalstraight end section 117E, wherein the distal' loop 117D and the distalstraight end section 117E have a greater resiliency than the resiliencyof the electrode-carrying proximal loop 117P. The pitch of the helicalform 122 of the distal assembly 117 is selected to provide a gentlepressure for ensuring contact of all of ring electrodes 119 with tissue.It is understood that tapering of the helical form 122 ensures that thesmaller distal loop 117D can fit into the tubular region or pulmonaryvein which ensures placement of accuracy of the larger proximal loop117P and the ring electrodes 119 carried thereon at an ostium 111 of thetubular region 113, e.g., a pulmonary vein. The greater flexibility ofthe distal loop 117D and the distal straight end section 117E providesan atraumatic leading element that guides distal assembly 117 into thetubular region or pulmonary vein and ensures placement accuracy of thedistal assembly.

The catheter 110 enters a patient's body through a guiding sheath thathas been inserted in a body cavity, such as a heart chamber. Due to theflexible construction of the distal assembly 117, the helical form 122readily straightens for insertion into the guiding sheath. When exposedand unconstrained, the distal assembly 117 reassumes the helical form122 which is maneuvered to engage the tissue surface frontally with someor all of the ring electrodes 119 on the proximal loop 117P contactingthe tissue surface simultaneously.

FIG. 12 is a schematic sectional view of heart 226, showing insertion ofcatheter 110 into the heart. To insert catheter 110, the user firstpasses a guiding sheath 240 percutaneously through the vascular systemand into right atrium 244 of the heart through ascending vena cava 242.The sheath penetrates through interatrial septum 248, typically via thefossa ovalis, into left atrium 246. Alternatively, other approach pathscan be used. Catheter 110 is then inserted through the guiding sheathuntil the distal assembly 117 of the catheter 110 extends past thedistal end of the guiding sheath 240 into the left atrium 246.

Operator aligns the longitudinal axis of guiding sheath 240 (and ofcatheter 110) inside left atrium 246 with the axis of one of pulmonaryveins. Alignment can be performed under fluoroscopic or other means ofvisualization. The user advances the catheter 110 distally toward thepulmonary vein so that the soft distal end 117E first enters thepulmonary vein, followed by the soft distal loop 117D, both of whichguide the positioning and placement of the electrode-carrying proximalloop 117P onto the ostium. The user can apply a force F in the axialdirection to press the proximal loop 117P onto the ostium to ensurecontact between the ring electrodes 119 and the tissue.

The operator can rotate the catheter 110 about its axis within theguiding sheath 240 so that the proximal loop 117P traces an annular patharound the inner circumference of the vein. Meanwhile, the user canactuate an RF generator to ablate the tissue in contact with the ARelectrodes along the path. Simultaneously, impedance and/or PV potentialrecordings can be made with the IR and/or RR electrodes. Aftercompleting this procedure around one pulmonary vein, the user can shiftthe sheath 240 and catheter 110 and repeat the procedure around one ormore of the other pulmonary veins.

Study Overview

This disclosure is more clearly understood with a corresponding studydiscussed more particularly below with respect to treatment of PAF. FIG.13 in particular provides a schematic overview of the subject studyprotocol of this disclosure as Appendix 3 and Appendix 4, each of whichare incorporated by reference in their entirety as if set forth verbatimherein. The purpose of this study was to establish the overall safetyand effectiveness of the catheter 24, in conjunction with the catheter110 and multi-electrode RF generator, for the isolation of the atrialpulmonary veins in treatment of subjects with drug refractory,symptomatic, paroxysmal atrial fibrillation is clinically safe andclinically effective.

The study is a prospective, multicenter, single arm clinical evaluationutilizing catheters 24 and 110. The sample size for the study isprimarily driven by the safety endpoint. An adaptive Bayesian design canbe used to determine the sample size based on the safety endpoint alone.Sample size selection interim analyses can be performed when 80, 130,180, and 230 evaluable subjects are enrolled in the main study (e.g.,mITT Population). Safety outcome at 30 days will be used as a proxy forthe primary safety endpoint at each interim. The final safety analysisis on complete follow-up for the primary safety endpoint for allevaluable patients in the main study. Predictive probabilities ofsuccess are used to determine whether the sample size at each interimanalysis will be sufficient or if the trial enrollment will continue.Sample size simulations were performed using performance goals of 15%and 80% respectively for the safety and effectiveness endpoint rates.

At the time of each interim analysis, predictive probabilities ofsuccess are estimated using the available data from all evaluablesubjects in the mITT population, assuming a non-informative uniformprior distribution for the primary safety rate. Enrollment is stopped ifthe predictive probability of trial success at any interim is greaterthan 90%, or if the predictive probability of trial success with themaximum sample size is less than a futility bound of 6.5%. Otherwise,enrollment continues until the next interim or the final sample size.Analysis of the effectiveness endpoint is performed at the final samplesize determined for the safety endpoint. Power for the effectivenessendpoint assessment is >80% at all sample sizes N30 subjects.

The primary safety and effectiveness endpoints are evaluated using exacttests for binomial proportions at a one-sided 5% significance level.

In order to control for operational bias, the timing and results of theinterim analyses are not revealed to study investigators unless aninterim analysis results in a decision to stop enrollment. The interimanalyses are conducted seamlessly with no interruption to studyenrollment unless indicated by an interim analysis. The predictedprobability of study success or summary results which are calculated atthe time of the interim analysis is not disseminated by the statisticianperforming the interim analysis until the time of the final databaselock for the CSR.

Analyses for primary effectiveness endpoint included null andalternative hypotheses, including Ho: PE<0.80 and Ha: PE>0.80. It isunderstood that primary effectiveness (PE) can mean proportion ofpatients with acute procedural success defined as confirmation ofentrance block in treated PVs after adenosine and/or isoproterenolchallenge (with or without the use of a focal catheter). Theper-protocol population is used as the primary analysis population.Subjects with missing effectiveness endpoints data will be excluded inthe primary analysis. Sensitivity analyses for missing data is performedusing the PP and population to assess the impact of missing data on theprimary effectiveness outcome and are described in the StatisticalAnalysis Plan (SAP).

With respect ablation parameters of the study, electrodes 33 of catheter24 can make contact with the tissue due to the balloon 80 and length ofthe electrodes, which each helps in accommodating variable anatomy. Thepower needed to create a circumferential contiguous lesion in the ostiumto the pulmonary vein is therefore less than that of other RF catheters.Power delivery from each electrode is regulated by the generator and isdetermined by user input and by the temperature read by the thermocouplelocated on the electrode.

When used with the catheter 24, the irrigation pump of the studydelivered a continuous infusion of 5 mL/minute of room temperatureheparinized saline (1 u heparin/1 mL saline) when not delivering RFcurrent. To inflate the balloon and during ablation, the high flowsetting was used to deliver 35 mL/minute. The recommended operatingparameters for the catheter 24 are presented in FIG. 14 .

The study duration is approximately 2.5 years; 1.5 years for theenrollment phase and an additional 1 year to complete follow-up. It isunderstood that data is presented herein for purposes of illustrationand should not be construed as limiting the scope of the disclosedtechnology in any way or excluding any alternative or additionalembodiments.

The study can demonstrate the clinical safety and acute effectiveness ofthe balloon catheter 24 when used with catheter 110 for the isolation ofthe atrial pulmonary veins in treatment of drug refractory ParoxysmalAtrial Fibrillation (PAF). Specifically, the study can demonstrate theclinical safety based on the incidence of early-onset (within 7 days ofablation procedure) primary adverse events (PAE). FIG. 15 shows a tablesummarizing intensity or severity of each AE assessed according toclassifications. The study can also demonstrate the long termeffectiveness based on the proportion of acute procedural success,whereby success in this context can be defined as confirmation ofentrance block in treated pulmonary veins after adenosine and/orisoproterenol challenge, including subjects with or without the use of afocal ablation catheter and/or with freedom from documentedAF/AT/Atypical (Left side) AFL episodes based on electrocardiographicdata through the effectiveness evaluation period (day 91-365 post indexprocedure). Subjects with drug refractory, symptomatic PAF were enrolledand the patient population size included a maximum of 310 evaluablesubjects (though fewer or more subjects could be investigated as neededor required, including populations such as 80, 130, and 180). Subjectscan be evaluated prior to the procedure, prior to discharge, and postprocedure at 7 days (4-10 days), 1 month (23-37 days), 3 months (76-104days), 6 months (150-210 days), and 12 months (316-406 days).

The primary objective of the study was demonstrating the clinical safetyand acute effectiveness of the balloon catheter 24 in conjunction withcatheter 110, in the isolation of the atrial pulmonary veins in for thetreatment of drug refractory PAF. Secondary objectives included todetermine the early-onset (within 7 days), peri-procedural (30 day), andlong-term (12 month) safety rates associated with the use of ballooncatheter 24, the acute procedural success, defined as confirmation ofentrance block in treated PVs after adenosine and/or isoproterenolchallenge, of the balloon catheter 24 (with or without the use of afocal catheter). Also to evaluate Health Economics outcomes and Qualityof Life (QoL) data for subjects treated with the balloon catheter 24,and to evaluate, within a subset of the Main Study population, thecomparative incidence of pre-procedure and post-procedure symptomaticand asymptomatic cerebral emboli, as determined by MRI evaluations. Thepresence of emboli-associated neurological deficits was evaluated, usingthe NIHSS, mRS, and general neurological assessments.

Primary endpoints of the study include acute effectiveness and acutesafety. Acute safety can include included incidence of early onsetPrimary Adverse Events (PAE) (within 7 days of an ablation procedurewhich used one or more of the investigational devices). Throughout thisdisclosure, it is understood that an adverse event (AE) is any untowardmedical occurrence in a subject whether or not related to theinvestigational medical device. For purposes of this disclosure, an AEcan be any undesirable experience (sign, symptom, illness, abnormallaboratory value, or other medical event) occurring to a subject duringthe course of the study, whether or not it is related to the device orprocedure. Physical findings (including vital signs) observed atfollow-up, or preexisting physical findings that worsen compared tobaseline, are adverse events if the investigator determines they areclinically significant. As to the study, any medical condition presentat the time that the subject is screened is considered as baseline andnot reported as an AE. Such conditions should be added to backgroundmedical history, if not previously reported. However, if the studysubject's condition deteriorates at any time during the study, it can berecorded as an AE.

Similarly, adverse events can be considered if any of the followingapply: event is cardiovascular in nature, the event is a serious adverseevent, causality is related to investigational device, ablationprocedure, or unknown in nature. In contrast, the following clinicalevents were not considered an adverse event for this study: minorpericarditis attributable to the ablation procedure defined as pleuriticchest discomfort with or without pericardial rub and ECG changes,AF/AFL/AT recurrence requiring pharmacological or synchronizedelectrical cardioversion during the hospitalization for the indexablation procedure, or throughout the duration of the study. However,new onset of left atrial flutter occurring post-ablation is an AE, andre-ablation for AF or pre-existing AFL/AT itself is not an AE, howeverany procedural complication is considered an AE and shall be reportedwithin the applicable timelines.

A serious adverse event (SAE) in this disclosure are those consideredany event that meets one or more of the following criteria: leads to adeath, leads to a serious deterioration in the health of a subject thatresulted in a life-threatening illness or injury, a permanent impairmentof a body structure or a body function, in-patient hospitalization orprolongation of an existing hospitalization, medical or surgicalintervention to prevent life-threatening illness or injury or permanentimpairment to body structure or a body function, leads to fetaldistress, fetal death or a congenital abnormality or birth defect. It isunderstood that planned hospitalization for a condition present prior tothe subject's enrollment in the study cannot meet the definition of anSAE. An AE would meet the criterion of “hospitalization” if the eventnecessitated an admission to a health care facility (e.g., an overnightstay). Emergency room visits that do not result in admission to thehospital were evaluated for one of the other serious outcomes. Forfurther reference, FIG. 15 is provided summarizing classifications forthe intensity or severity of each AE.

In the study, PAEs included the following AEs: device or procedurerelated death, Atrio-Esophageal Fistula, Myocardial Infarction, CardiacTamponade/Perforation, Thromboembolism Stroke/ Cerebrovascular Accident(CVA), Transient Ischemic Attach (TIA), Phrenic Nerve Paralysis,Pulmonary Vein Stenosis, Pericarditis, Pulmonary Edema, Major VascularAccess Complication/Bleeding, and Hospitalization (initial orprolonged). In the study, events were considered as primary AEs even ifthey occur greater than one week (7 days) post-procedure. Events relatedto hospitalization were excluded solely due to arrhythmia recurrence ornon-medically urgent cardioversion.

Secondary endpoints of the study as to safety included incidence ofindividual PAEs from the primary composite, incidence of Unanticipated(Serious) Adverse Device Effects (USADEs), incidence of Serious AdverseEvents (SAEs) within 7 days (early-onset), >7-30 days (peri-procedural),and >30 days (late onset) of initial ablation procedure, incidence ofnon-serious adverse events, acute procedural success defined asconfirmation of entrance block in treated pulmonary veins (PVs) afteradenosine challenge (with or without the use of a focal catheter),pulmonary vein isolation (PVI) touch-up by focal catheter among alltargeted veins and by subject during the index procedure, use of focalcatheter ablation for non-PV triggers during the index procedure,freedom from documented AF/AT/Atypical (left-side) AFL episodes based onelectrocardiographic data through the effectiveness evaluation period(day 91-365 post index procedure) off Class I and III AADs, averagenumber of RF applications, and RF time, required to isolate commonpulmonary veins, incidence of hospitalization for cardiovascular events(with hospitalization defined as prolonged stay ≥2 nights post standardindex procedure or in-patient stay not concurrent with index procedure≥1 calendar day), Health Economics data including but not limited toindex procedure workflow costs, Quality of Life (QoL), and hospitalcost, incidence of pre-procedure and post-ablation asymptomatic andsymptomatic cerebral emboli as determined by MRI evaluations inNeurological Assessment Evaluable (NAE) subjects, frequency, anatomiclocation, and size (diameter and volume) of cerebral emboli by MRIevaluations at baseline, post-ablation and during follow-up (if newlesions observed) in NAE subjects, incidence of new or worseningneurologic deficits at baseline, post-ablation and follow-up in NAEsubjects, Summary of National Institutes of Health Stroke Scale (NIHSS)and Modified Rankin Scale (mRS) scores at baseline, post-ablation andduring follow-up, summary of MoCA scores at baseline, 1 month follow-upand during further follow-up, and hospitalization for cardiovascularevents (hospitalization defined as prolonged stay nights post indexprocedure or in-patient stay not concurrent with index procedure 1calendar day (if lesions were identified in prior evaluation) in NAEsubjects.

Secondary endpoints of the study as to effectiveness included percentage(%) of PVI touch-up by focal catheter among all targeted veins and bysubject; percentage (%) of subjects with use of focal catheter ablationfor non-PV triggers; percentage (%) of subjects with freedom fromdocumented, symptomatic atrial fibrillation (AF), atrial tachycardia(AT), or atypical (left side) atrial flutter (AFL) episodes(episodes >30 seconds on arrhythmia monitoring device from day 91 to180); and percentage (%) of subjects with freedom from documented,atrial fibrillation (AF), atrial tachycardia (AT), or atypical (leftside) atrial flutter (AFL) episodes (episodes >30 seconds on arrhythmiamonitoring device from day 91 to 180).

Secondary endpoints of the study as to additional analyses on proceduralcharacteristics, including but not limited to total procedure time,ablation time, RF application time, balloon dwell time, time to effectPVI, number and time of RF applications per PV location, and fluoroscopytime and dose.

Secondary endpoints of the study as to health economic assessmentsincluded index procedural workflow costs, hospital costs, and quality oflife.

NAE safety endpoints include incidence of pre-procedure andpost-ablation asymptomatic and symptomatic cerebral emboli as determinedby MRI evaluations in NAE subjects; frequency, anatomic location, andsize (diameter and volume) of cerebral emboli by MRI evaluations atbaseline, post-ablation and during follow-up (if new lesions observed)in NAE subjects; incidence of new or worsening neurologic deficits atbaseline, post-ablation and follow-up in NAE subjects; and summary ofNIHSS and mRS scores at baseline, post-ablation and during follow-up (iflesions were identified in prior evaluation) in NAE subjects.

Subjects enrolled in a NAE subgroup are assessed for incidences ofsymptomatic and asymptomatic pre-ablation and post-ablation cerebralemboli, with either an absence of neurological symptoms (asymptomatic)or with emboli-associated neurological symptoms (symptomatic). The NAEsubgroup is a prospective design with consecutive enrollment. Roll-insubjects can NOT be eligible for the NAE subgroup. This approachminimizes the confounding influence of a learning curve during early useof a medical device. The sample size of 40 subjects in this subgroup canprovide at least 95% probability of observing at least one event if thetrue ACE rate is greater than or equal to 8%. Enrollment in the NAEsubgroup can be terminated prior to achieving the target 40 subjects ifstudy enrollment ends early after a planned interim look.

Subjects enrolled in the Modified Intent-To-Treat (mITT) populationincluded enrolled subjects meeting eligibility criteria and had thestudy catheter inserted. The safety population (SP) included allenrolled subjects who have undergone insertion of the study catheter.The Per Protocol (PP) Population was a subset of the mITT population andincluded subjects enrolled and meet all eligibility criteria, hadundergone RF ablation with the study catheter, and had been treated forthe study-related arrhythmia.

Primary effectiveness endpoints as to clinical effectiveness in thestudy was determined by those events where there was freedom fromdocumented AF, atrial tachycardia (AT), or Atypical (left-side) atrialflutter (AFL) episodes (e.g., >30 seconds on arrhythmia monitoringdevice) based on electrocardiographic data through the effectivenessevaluation period (day 91-365 post index procedure). Additionally, if asubject met any one of the following criteria, then the subject wasconsidered as chronic effectiveness failure: Acute procedural failure(i.e., failure to confirm entrance block in clinically relevantpulmonary veins post-procedure), repeat ablation or surgical treatmentfor AF/AT/Atypical (left-side) AFL after the blanking period (after day90 post index procedure), DC cardioversion for AF/AT/Atypical(left-side) AFL after the blanking period (after day 90 post indexprocedure), continuous AF/AT/AFL on a standard 12-lead ECG even if therecording is less than 30 seconds in duration (after day 90 post indexprocedure), a new Class I and/or Class III AAD is prescribed for AFduring effectiveness evaluation period (e.g., day 91-365 post indexprocedure) or prescribed during the blanking period and continued past90 days, a previously failed Class I and/or Class III AAD (failed at orbefore screening) was taken for AF at a greater dose than the highestineffective historical dose during the effectiveness evaluation period(e.g., day 91-365 post index procedure), and amiodarone was prescribedpost index ablation procedure.

During this study, current AF management guidelines and theinstitution's standard of care practices are followed as closely aspossible for AAD therapy. FIG. 16 shows a table illustratingclassifications based on AAD therapy administered in the blanking andpost-blanking periods in the study.

It is understood that prior to the procedure, uninterruptedanticoagulation therapy was in place at least 1 month prior to theablation procedure. If receiving warfarin/coumadin therapy, subjects hadan international normalized ratio (INR) ≥2 for at least 3 weeks prior totreatment and the subject's must be confirmed to be ≥2 within 48 hourspre-procedure. Any INR<2 within 3 weeks prior to ablation was understoodto lead to exclusion of the subject or postponement of the studyprocedure until the INR is ≥2 for at least 3 weeks prior to treatment.

Anticoagulation therapy was not interrupted or stopped prior to theprocedure (e.g., no doses should be missed or omitted) and daily regimenwas continued. During the procedure, a heparin bolus was administeredprior to transseptal puncture an ACT of 350-400 was targeted secondsprior to inserting the balloon 80 and throughout the procedure. ACTlevels were checked every 15-30 minutes during the procedure to ensurean ACT target of 350-400 seconds. All recordings (ACT level, timing ofheparin administration and dose) were documented in the medical recordsas source documentation. All tubing and sheath was continuously flushedwith heparinized saline.

After the procedure, anticoagulation therapy was strongly recommendedfor at least 2 months following ablation. Additional medications neededto treat clinical indications were at the discretion of the clinicalinvestigation physician AAD management during the study was at thediscretion of the investigator.

Secondary effectiveness endpoints included acute procedural successdefined as confirmation of entrance block in treated PVs after adenosinechallenge (with or without the use of a focal catheter), PVI touch-up byfocal catheter among all targeted veins and by subject during the indexprocedure, use of focal catheter ablation for non-PV triggers during theindex procedure, freedom from documented symptomatic AF/AT/Atypical(left-side) AFL episodes based on electrocardiographic data through theeffectiveness evaluation period (day 91-365 post index procedure) offType I and III antiarrhythmic drugs (AADs), and average number of RFapplications, and RF time, required to isolate common pulmonary veins.

Patient Selection

The criteria for patient selection, method or uses, personnel,facilities, and training specified in this study were intended tominimize the risk to subjects undergoing this procedure.

Patients were prescreened carefully prior to enrollment in the study toensure compliance with the inclusion and exclusion criteria. The risk ofPNP was minimized by monitoring the PN with pacing maneuvers before theablation. Ablation was stopped immediately if evidence of PN impairmentis observed, and the balloon can be repositioned. The risk of PVstenosis can be minimized by not positioning the balloon within thetubular portion of the target PV. The balloon should not be inflatedwhile the catheter is positioned inside the pulmonary vein; rather, itis always to be inflated in the atrium, then positioned at the PVostium.

The risk of an embolus in the study was reduced by quickly terminatingthe application of current after an impedance rise, which limits thesize of the coagulum on the electrode. It has been observed that thrombican form on the transseptal sheath almost immediately after crossing theseptum. Optimal anti-coagulation, using Heparin to achieve an ACT of 350seconds, during procedure and early Heparin administration, prior totransseptal puncture, can substantially decreases the risk. This riskcan be reduced by the use anticoagulant therapy, at the discretion ofthe investigator.

The risk of ACE can be minimized by implementing an anti-coagulationregimen prior to balloon introduction into the left atrium and duringprocedure to avoid thrombi/emboli during procedure. Investigators areinstructed to remove air bubbles and to minimize catheter exchangeduring procedure to mitigate the of risk air introduction. A singletransseptal technique, with administration of heparin bolus prior totransseptal puncture, is also implemented. In order to help preventesophageal injury, intraluminal esophageal temperature monitoring isrequired for the study to ensure the physician has accurate informationabout the location of the esophagus relative to intended sites ofablation.

Following procedures, all subjects are maintained on systemic oralanticoagulation therapy for at least two months post-procedure,beginning within 6 hours post-procedure. After two-monthspost-procedure, a decision regarding continuation of systemicanti-coagulation agents is made based on the subject's risk forthromboembolism. Systemic oral anticoagulation can be continued beyondtwo-months post-ablation in subjects with CHA₂DS₂-VASc score≥2.

For each included patient, age, gender and cardiovascular risk factors(e.g., diabetes mellitus, obesity, smoking, high blood pressure,hyperlipidemia) were recorded. Initial imaging was brain CT withcervical and intracranial angiography or brain MRI with time of flightangiography, depending on hospital protocol. The ASPECT (Alberta StrokeProgram Early CT) score was evaluated by experienced neuroradiologistson either modality, and the NIHSS score by neurologists. Patients weretreated up to 12 hours from time of stroke onset or time last known wellin case of wake-up stroke.

Inclusion criteria for the study included the following:

-   -   Diagnosed with Symptomatic PAF;    -   Selected for AF ablation procedure for pulmonary vein isolation;        Able and willing to comply with uninterrupted per-protocol    -   Diagnosed with Symptomatic PAF, including at least three (3)        symptomatic episodes of AF with attacks lasting ≥1 minute)        within six (6) months prior to enrollment, and at least one (1)        AF episode must be electrocardiographically documented within        twelve (12) months prior to enrollment. Electrocardiographic        documentation can include, but is not limited to,        electrocardiogram (ECG), Holter monitor, or telemetry strip;    -   Failing at least one (1) Class I or Class III AAD as evidenced        by recurrent symptomatic AF or intolerable side effects to the        AAD;    -   Willingness to comply with anticoagulation requirements (e.g.,        warfarin, rivaroxaban, dabigatran, apixaban);    -   Age 18-75 years; and    -   Able and willing to comply with all pre-procedure,        post-procedure, and follow-up testing and visit requirements.

Exclusion criteria for the study included the following:

-   -   AF secondary to electrolyte imbalance, thyroid disease, or        reversible or non-cardiac cause;    -   Previous surgical or catheter ablation for AF;    -   Patients known to require ablation outside the PV ostia and CTI        region (e.g. AVRT, AVNRT, atrial tachycardia, VT and WPW);    -   Previously diagnosed with persistent or long-standing persistent        AF and/or Continuous AF>7 days, or >48 hrs terminated by        cardioversion;    -   Any percutaneous coronary intervention within the past 2 months;    -   Valve repair or replacement or presence of a prosthetic valve;    -   Any carotid stenting or endarterectomy within the past 6 months;    -   Any carotid stenting or endarterectomy;    -   Coronary artery bypass grafting (CABG), cardiac surgery (e.g.        ventriculotomy, atriotomy), or valvular cardiac surgical or        percutaneous procedure within the past 6 months;    -   Documented left atrium (LA) thrombus within 1 day prior to the        index procedure;    -   LA antero posterior diameter >50 mm;    -   Any PV with a diameter 26 mm    -   Left Ventricular Ejection Fraction (LVEF) <40%;    -   Contraindication to anticoagulation (e.g. heparin);    -   History of blood clotting or bleeding abnormalities;    -   Myocardial infarction within the past 2 months;    -   Documented thromboembolic event (including transient ischemic        attack) within the past 12 months;    -   Rheumatic Heart Disease;    -   Uncontrolled heart failure or New York Heart Association (NYHA)        function class III or IV;    -   Awaiting cardiac transplantation or other cardiac surgery within        the next 12 months;    -   Unstable angina;    -   Acute illness or active systemic infection or sepsis;    -   Diagnosed atrial myxoma or presence of an interatrial baffle or        patch;    -   Presence of implanted pacemaker or implantable cardioverter        defibrillator (ICD), or tissue-embedded, iron-containing metal        fragments);    -   Significant pulmonary disease, (e.g. restrictive pulmonary        disease, constrictive or chronic obstructive pulmonary disease)        or any other disease or malfunction of the lungs or respiratory        system that produces chronic symptoms;    -   Significant congenital anomaly or medical problem that, in the        opinion of the investigator, would preclude enrollment in this        study;    -   Women who are pregnant (as evidenced by pregnancy test if        pre-menopausal), lactating, or who are of child bearing age and        plan on becoming pregnant during the course of the clinical        investigation;    -   Enrollment in an investigational study evaluating another        device, biologic, or drug;    -   Has known pulmonary vein stenosis;    -   Presence of intramural thrombus, tumor or other abnormality that        precludes vascular access, or manipulation of the catheter;    -   Presence of an inferior vena cava filter;    -   Presence of a condition that precludes vascular access;    -   Life expectancy or other disease processes likely to limit        survival to less than 12 months;    -   Presenting contra-indication for the devices (e.g. TTE, CT,        etc.) used in the study, as indicated in the respective        instructions for use;    -   Categorized as a vulnerable population and requires special        treatment with respect to safeguards of well-being    -   Additional exclusion criteria for Neurological Assessment        Evaluable (NAE) subjects include contraindication    -   Patient on amiodarone at any time during the past 3 months prior        to enrollment;    -   Contraindication to use of contrast agents for MRI such as        advanced renal disease;    -   Presence of iron-containing metal fragments in the body; and    -   Unresolved pre-existing neurological deficit.

Results of the Study

In the study, 95 patients were treated. Patients (age 60.3±9.81 yrs,64.2% male) underwent PVI at 6 centers using a multielectrode RF ballooncatheter (RFB). Eight subjects were enrolled as part of the roll-inphase. Main population consisted of 87 subjects of whom two wereconsidered to be ineligible, resulting in an evaluable cohort of 85subjects. Acute success, a primary effectiveness endpoint of the study,was defined as sustained PV entrance block upon Adenosine/Isoproterenolchallenge. Single-shot success was defined as PVI before adenosinechallenge with one valid 60 second ablation. Time to isolation was theobserved RF ablation time to reach a pure single-shot success.Recurrence of symptomatic AF/AT/AFL was documented with weeklytranstelephonic monitoring from 3-6 months, and Holter monitoring at 6months.

During the study, investigators collected the following data: RFablation parameters per PV, number of RF application(s) per target PV,number of RF application(s) required with a focal catheter (ifapplicable), total RF duration per target PV, total time of RFapplication with the balloon catheter 24 until PV isolation of targetedvein was achieved (TTI=time to isolate), total time of RF applicationwith the focal catheter (if applicable), PV acute reconnection, RFablation parameters per application, Targeted vein, Ablation number ofthe generator, Total Duration of RF energy per application, BalloonInflation Index prior to target PV application, Identification ofposterior and/or pacing electrodes, Ablation parameters (impedance,temperature, power, number of active electrodes per application, andtotal duration of RF application. Also, RF duration ofposterior/anterior electrode, etc.) can be collected during the ablationprocedure via the generator log files, ablation parameters, PV isolationinformation, including but not limited to percentage of targeted PVisolated on first shot, RF application and percentage of targeted PVwith acute reconnection on adenosine (ATP) and/or isoproterenolchallenge, procedural parameters, including but not limited to: Durationof time in mapping (LA and PVs), Total RF duration (consecutive time ofRF energy delivered by multi-electrode RF balloon catheter and focalcatheter (if applicable)), Total PVI time with balloon catheter(Duration of time from 1^(st) RF application to final RF application),Total PVI time with focal catheter (if applicable), Total procedure time(from first femoral puncture to catheter removal), Total fluoroscopytime and dose, Total Balloon dwell time (from first RF balloon insertionuntil RF balloon removal), ECG data, Total fluid delivered via ablationcatheter, Total fluid delivered via intravenous line (if captured),Fluid output (if captured), Net Fluid input, ACT level and timepoint ofheparin administration, Strategy to evaluate the proximity to thephrenic nerve, Strategy used to minimize risk of esophageal injury, Typeof temperature probe, cut-off temperature and any abnormal increases intemperature observed.

Ablation procedures were performed under general anesthesia in 47/87(54.0%) subjects, and under conscious sedation in 40/87 (45.9%)subjects. One primary AE (retroperitoneal bleed) occurred in 1/85 (1.2%)patient. Acute success was achieved in all 82 evaluable pts (100%)undergoing Aden/Iso challenge; 3 pts did not receive Aden/Iso challengeand were excluded from this analysis. Single-shot successes were 74.7%,57.9%, 72.3%, and 68.7% for the LIPV, LSPV, RIPV, and RSPV. Time toisolation per vein was 8.2±4.95, 10.6±7.71, 8.7±4.70 and 8.8±6.45 secfor the LIPV, LSPV, RIPV, and RSPV, respectively. Ablations wereperformed with procedure time 87.6±22.25 min, RF time 6.1±2.37 min, with7.5±3.25 RF applications, RFB LA dwell time 40.3±16.69 min, andfluoroscopy time 10.9±9.12 min. After the first roll-in cases, the totalprocedure and fluoroscopy times decreased to 76.0 min and 10.5 min. TheKaplan-Meier estimate of freedom from documented symptomatic AF/AT/AFLrecurrence at 6 months was 80.9% (standard error [SE], 4.3% as shown inFIG. 17 ).

In a prior study feasibility study using the multi-electrode ballooncatheter of this disclosure that included 40 enrolled patients, enrolledpatients were similarly screened for silent cerebral lesions (SCL), alsoknown as ACE. A secondary analysis of the results of the first study ofthis disclosure and the prior study evaluated the impact of certainablation workflow modifications on the incidence of SCL following PVIwith the herein described multi-electrode RF balloon catheter inpatients with symptomatic PAF.

In the prior study, the ablation workflow included (1) irrigation flowrate during RF application: 35 mL/minute, (2) maximum power setting: 15W, (3) maximum temperature setting: 65° C. (maximum temperature loweredto 60° C. after 7 patients), (4) maximum application time anteriorelectrodes: 60 seconds, and (5) maximum application time posteriorelectrodes: 20 seconds.

In contrast, the first study of this study included an ablation workflowas follows: (1) eliminating dual trans-septal access, (2) using anover-the-wire mini lasso, (3) continuously irrigating all side ports,(4) bolus dosing with heparin before trans-septal puncture, (5)maintaining activated clotting time (ACT) at 350 to 400 seconds, and (6)maximum temperature setting: 55° C. An example ablation workflow for thefirst study of this disclosure is shown in FIG. 18 .

Analyses of MRI data were performed in the neurologicassessment-evaluable (NAE) analysis population, which included allenrolled patients who met eligibility criteria, had catheter 24 of thisdisclosure inserted, received RF energy, completed the pre- andpost-ablation brain MRI examinations, and completed ≥1 post-ablationneurologic assessment. Incidences of SCL were evaluated usingdiffusion-weighted MRI 72 hours prior to the ablation procedure, as wellas within 48 hours post-procedure.

In the prior study and the first study, patients with identifiablelesions or neurologic symptoms had a follow-up MRI to determine lesionprogress, until lesions were resolved. The anatomic location and size(diameter and volume) of SCL determined by MRI evaluations were alsorecorded. All patients underwent neurologic and cognitive assessments,including NIHSS assessments. In the NAE populations of the 2 studies,the prior study (N=38) and the first study (N=31), mean (standarddeviation) ages were 60.8 (10.04) and 59.3 (8.08) years, respectively,and 57.9% and 71.0% of patients, respectively, were male, as shown inFIG. 18 . SCL incidences at discharge were 23.7% (10 lesions in 9patients) in the prior study and 9.7% (3 lesions in 3 patients) in thefirst study of this disclosure as seen in FIG. 19A. FIG. 19B in contrastshows a graph summarizing mean activated clotting time in patients withand without silent cerebral lesion from the first study of thisdisclosure compared with a prior study.

In the depicted results, it can be seen that modifications to theablation workflow between the prior study and the first study of thisdisclosure led to a substantially lower incidence of SCL following PAFablation using the RF balloon catheter of this disclosure. Thesereductions in the incidence of SCL were accompanied by a lower incidenceof minor stroke. In addition, patients in the first study had higher ACTthan patients in the prior study. Taken together, these results suggestthat the modifications to the ablation workflow, including stringentanticoagulation control, eliminating dual trans-septal access, andreducing the maximum temperature setting to 55° C., in the first studycontributed to lower incidence of SCL.

FIG. 20 depicts a method or use 2000 for administering a procedure fortreating atrial fibrillation. The method or use 2000 can include 2010delivering a multi-electrode radiofrequency balloon catheter to one ormore targeted pulmonary veins; 2020 ablating tissue of the pulmonaryvein using the multi-electrode radiofrequency balloon catheter; and 2030achieving a predetermined effectiveness rate of pulmonary veinisolation.

FIG. 21 depicts a method or use 2100 for administering a procedure fortreating atrial fibrillation. The method or use 2100 can include 2110delivering a multi-electrode radiofrequency balloon catheter to one ormore targeted pulmonary veins; 2120 ablating tissue of the pulmonaryvein using the multi-electrode radiofrequency balloon catheter; and 2130achieving a predetermined success rate of pulmonary vein isolation.

FIG. 22 depicts a method or use 2200 for administering a procedure fortreating atrial fibrillation. The method or use 2200 can include 2210delivering a multi-electrode radiofrequency balloon catheter to one ormore targeted pulmonary veins; 2220 ablating tissue of the pulmonaryvein using the multi-electrode radiofrequency balloon catheter; and 2230achieving pulmonary vein isolation and at least a 97% safety endpointwithin seven (7) days of successful pulmonary vein isolation.

FIG. 23 depicts a method or use 2300 for administering a procedure fortreating atrial fibrillation. The method or use 2300 can include 2310delivering a multi-electrode radiofrequency balloon catheter to one ormore targeted pulmonary veins; 2320 ablating tissue of the pulmonaryvein using the multi-electrode radiofrequency balloon catheter; and 2330achieving pulmonary vein isolation and at least a 90% safety endpointwithin seven (7) days of successful pulmonary vein isolation.

FIG. 24 depicts a method or use 2400 to treat a plurality of patientsfor paroxysmal atrial fibrillation. The method or use 2400 can includedelivering a multi-electrode radiofrequency balloon catheter having aplurality of independently controllable electrodes for radiofrequencyablation and a multi-electrode diagnostic catheter to one or moretargeted pulmonary veins; 2420 ablating tissue of the one or moretargeted pulmonary veins with one or more of the plurality of theelectrodes independently controlled multi-electrode radiofrequencyballoon catheter; 2430 diagnosing the one or more targeted pulmonaryveins using the multi-electrode diagnostic catheter; and 2440 achievingat least one of a predetermined clinical effectiveness and acuteeffectiveness of the method or use based on use of the multi-electroderadiofrequency balloon catheter and the multi-electrode diagnosticcatheter in the isolation of the one or more targeted pulmonary veins.

FIG. 25 depicts a method or use 2500 to treat a plurality of patientsfor paroxysmal atrial fibrillation. The method or use 2500 can include2510 delivering a multi-electrode radiofrequency balloon catheter havinga plurality of independently controllable electrodes for radiofrequencyablation and a multi-electrode diagnostic catheter to one or moretargeted pulmonary veins; 2520 ablating tissue of one or more targetedpulmonary veins with one or more of the plurality of the electrodesindependently controlled multi-electrode radiofrequency ballooncatheter; 2530 diagnosing all targeted pulmonary veins using themulti-electrode diagnostic catheter; and 2540 achieving a predeterminedrate of adverse events based on use of the multi-electroderadiofrequency balloon catheter and the multi-electrode diagnosticcatheter in the isolation of all targeted pulmonary veins, during andapproximately 6 months after the method or use.

FIG. 26 depicts a method or use 2600 to treat a plurality of patientsfor paroxysmal atrial fibrillation. The method or use 2600 can include2610 evaluating a number and size of all targeted pulmonary veins andanatomy of the left atrial; 2620 puncturing the trans septal; 2630selectively positioning a multi-electrode esophageal temperaturemonitoring device in the vasculature with respect to all targetedpulmonary veins; 2640 selectively positioning a multi-electroderadiofrequency balloon catheter in the vasculature with respect to alltargeted pulmonary veins, the multi-electrode radiofrequency ballooncatheter having a plurality of independently controllable electrodes forradiofrequency ablation; 2650 ablating tissue of all targeted pulmonaryveins with one or more of the plurality of the electrodes independentlycontrolled multi-electrode radiofrequency balloon catheter; 2660confirming isolation of all targeted pulmonary veins using themulti-electrode diagnostic catheter; 2670 confirming existence of anentrance block in all targeted pulmonary veins; and 2680 achieving apredetermined clinical effectiveness and/or acute effectiveness of themethod or use, based on the confirmed existence of the entrance block,regarding the isolation of all targeted pulmonary veins following themethod or use.

FIG. 27 depicts a method 2700 to treat a plurality of patients forparoxysmal atrial fibrillation. The method 2700 can include 2710administering a heparin bolus prior to transseptal puncture; 2720providing transseptal access for a multi-electrode radiofrequencyballoon catheter and a mapping catheter across a septum; 2730 using alasso catheter for at least one septum puncture; 2740 irrigating, by theballoon catheter, continuously at or about all targeted veins; 2750confirming activated clotting time between approximately about 350 and400 seconds prior to inserting the balloon catheter into a left atrium;and 2760 performing pulmonary vein ablation with the balloon catheterwith a maximum temperature setting of the balloon catheter beingapproximately about 55° C. thereby achieving at least one of apredetermined clinical effectiveness and acute effectiveness of themulti-electrode radiofrequency balloon catheter in the isolation of thetargeted pulmonary veins, during and approximately 3 months afterablation.

The method or uses, systems, and devices of this disclosure demonstratedhigh rates of substantial clinical effectiveness and safety in patientssuffering from PAF. The specific configurations, choice of materials andthe size and shape of various elements can be varied according toparticular design specifications or constraints requiring a system ormethod or use constructed according to the principles of the disclosedtechnology. Such changes are intended to be embraced within the scope ofthe disclosed technology. The presently disclosed embodiments,therefore, are considered in all respects to be illustrative and notrestrictive. It will therefore be apparent from the foregoing that whileparticular forms of the disclosure have been illustrated and described,various modifications can be made without departing from the spirit andscope of the disclosure and all changes that come within the meaning andrange of equivalents thereof are intended to be embraced therein.

The following clauses list non-limiting embodiments of the disclosure:

1. A method or use to treat a plurality of patients for paroxysmalatrial fibrillation, the method or use comprising the steps of:

delivering a multi-electrode radiofrequency balloon catheter having aplurality of independently controllable electrodes for radiofrequencyablation and a multi-electrode diagnostic catheter to one or moretargeted pulmonary veins;

ablating tissue of the one or more targeted pulmonary veins with one ormore of the plurality of the electrodes independently controlledmulti-electrode radiofrequency balloon catheter;

diagnosing the one or more targeted pulmonary veins using themulti-electrode diagnostic catheter; and

achieving at least one of a predetermined clinical effectiveness andacute effectiveness of the multi-electrode radiofrequency ballooncatheter and the multi-electrode diagnostic catheter in the isolation ofthe one or more targeted pulmonary veins, during and approximately 3months after the ablating step.

2. The method or use of clause 1, wherein acute effectiveness is definedby confirming if there is an entrance block in all targeted pulmonaryveins after adenosine and/or isoproterenol challenge.

3. The method or use of clause 2, further comprising: determining theacute effectiveness determined at approximately 3 months after theablating step; and

generating an estimated acute effectiveness at approximately 12 monthsafter the ablating step based on the acute effectiveness determined atapproximately 3 months.

4. The method or use of clause 3, wherein the estimated acuteeffectiveness at approximately 12 months is substantially similar to theacute effectiveness determined at approximately 3 months.

5. The method or use of clause 2, wherein the acute effectiveness isfurther defined by success greater than 90% for the plurality ofpatients.

6. The method or use of clause 2, wherein the acute effectiveness isfurther defined by success greater than 95% for the plurality ofpatients.

7. The method or use of clause 2, wherein a Type-1 error rate for powerthe acute effectiveness and the clinical effectiveness of all targetedveins are controlled at approximately a 5% level, the method or usefurther comprising:

determining whether the ablating is clinically successful for theplurality of patients if both the acute effectiveness and the clinicaleffectiveness indications are controlled at approximately the 5% level.

8. The method or use of clause 2, wherein the acute effectiveness is atleast 80% for the plurality of patients being at least 80 patients.

9. The method or use of clause 2, wherein the acute effectiveness is atleast 80% for the plurality of patients being at least 130 patients.

10. The method or use of clause 2, wherein the acute effectiveness is atleast 80% for the plurality of patients being at least 180 patients.

11. The method or use of clause 2, wherein the acute effectiveness is atleast 80% for the plurality of patients being at least 230 patients.

12. The method or use of clause 2, wherein the acute effectiveness isfurther defined by confirming if there is an entrance block in alltargeted pulmonary veins after adenosine and/or isoproterenol challengeusing a focal ablation catheter.

13. The method or use of clause 2, wherein the acute effectiveness isfurther defined by confirming if there is an entrance block in alltargeted pulmonary veins after adenosine and/or isoproterenol challengewithout using a focal ablation catheter.

14. The method or use of clause 1, wherein the ablating is administeredon the plurality of patients diagnosed with symptomatic paroxysmalatrial fibrillation.

15. The method or use of clause 1, wherein the step of diagnosingfurther comprises:

electrophysiological mapping of the heart.

16. The method or use of clause 1, wherein the multi-electrodediagnostic catheter further comprises a high torque shaft with ahalo-shaped tip section containing a plurality of pairs of electrodesvisible under fluoroscopy.

17. The method or use of clause 1, wherein the plurality of patients isat least 80.

18. The method or use of clause 1, wherein the plurality of patients isat least 130.

19. The method or use of clause 1, wherein the plurality of patients isat least 180.

20. The method or use of clause 1, wherein the plurality of patients isat least 230.

21. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by ulceration being absent in the plurality ofpatients after the ablating.

22. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a complication rate of approximately 13% orfewer of the plurality of patients experiencing esophageal erythemaafter the ablating.

23. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a complication rate of approximately 25% orfewer of the plurality of patients experiencing new asymptomaticcerebral embolic lesions after the ablating.

24. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a complication rate of approximately 20% orfewer of the plurality of patients experiencing new asymptomaticcerebral embolic lesions after the ablating.

25. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a complication rate of approximately 5-9% orfewer of the plurality of patients experiencing a primary adverse eventby approximately 7 or more days after the ablating.

26. The method or use of clause 1, wherein inclusion criteria for theplurality of patients comprises:

a diagnosis with symptomatic paroxysmal atrial fibrillation; and

a patient capability to comply with uninterrupted per-protocolanticoagulation requirements.

27. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a total procedure time.

28. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a total ablation time.

29. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a total RF application time.

30. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a total dwell time of the multi-electroderadiofrequency balloon catheter.

31. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a total time to isolate all targetedpulmonary veins.

32. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a number and a total time of applications bythe multi-electrode radiofrequency balloon catheter per location of alltargeted pulmonary veins.

33. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a number and a total time of applications bythe multi-electrode radiofrequency balloon catheter per patient.

34. The method or use of clause 1, wherein the predetermined acuteeffectiveness is defined by a number and a total time of applications bythe multi-electrode radiofrequency balloon catheter per targeted vein.

35. The method or use of any previous clause, wherein themulti-electrode radiofrequency balloon catheter comprises:

a compliant balloon with a plurality of electrodes bonded configured todeliver RF energy to tissue of the pulmonary vein and sense temperatureat each electrode.

36. The method or use of clause 1, wherein clinical effectiveness isdefined by an incidence of early onset of one or more adverse eventswithin a predetermined time of the method or use being implemented.

37. The method or use of clause 36, wherein the predetermined time is atleast 7 days.

38. The method or use of clause 36, wherein the one or more adverseevents comprise: death, atrio-esophageal fistula, myocardial infarction,cardiac tamponade/perforation, thromboembolism, stroke, TIA (TransientIschemic Attack), phrenic nerve paralysis, pulmonary vein stenosis, andthe major vascular access bleeding.

39. The method or use of clause 36, wherein the one or more adverseevents comprise: incidence of individual adverse events from a primarycomposite; incidence of serious adverse device effect; incidence ofserious adverse events within 7 days, at least 7¬30 days, and at least30 days following the ablating; incidence of non-serious adverse events;incidence of pre-and post-ablation asymptomatic and symptomatic cerebralemboli as determined by MRI evaluation; and frequency, anatomiclocation, and size (diameter and volume) of cerebral emboli by MRIevaluations at baseline, post-ablation and during follow-up.

40. The method or use of clause 36, wherein the one or more adverseevents for approximately 5-9% of the plurality of patients, the one ormore adverse events comprising:

NIHSS (National Institute of Health Stroke Scale) scores at baseline,post-ablation and during follow-up;

a summary of MoCA (Montreal Cognitive Assessment) and mRS (ModifiedRanking Scale) scores at baseline, 1 month and during further follow-up;a rate of hospitalization for cardiovascular events; a percentage (%) ofpulmonary vein isolation touch-up by focal catheter among the one ormore targeted veins;

a percentage (%) of subjects with use of focal catheter ablations fornon-PV triggers;

a percentage (%) of subjects with freedom from documented symptomaticatrial fibrillation (AF), atrial tachycardia (AT), or atypical (leftside) atrial flutter (AFL) episodes (episodes >30 seconds on arrhythmiamonitoring device from day 91 to 180);

a percentage (%) of subjects with freedom from documented atrialfibrillation (AF), atrial tachycardia (AT), or atypical (left side)atrial flutter (AFL);

one or more episodes that endure for 30 or more seconds on an arrhythmiamonitoring device from day 91 to 180 following the ablating; and

one or more procedural parameters including total procedure and ablationtime, balloon dwell time, RF application time, a number of RFapplications, fluoroscopy time and dose.

41. The method or use of clause 1, wherein the acute safety rateincludes complication rates of 10% or less and is defined by incidenceof asymptomatic cerebral embolic lesions at a discharge magneticresonance imaging (MRI).

42. The method or use of clause 1, wherein the acute effectiveness rateis 100% and is defined by electrically isolating all targeted pulmonaryveins without use of a focal ablation catheter.

43. The method or use of clause 1, wherein the acute effectiveness rateis defined by a freedom from documented atrial fibrillation, atrialtachycardia, or atypical atrial flutter episodes based onelectrocardiographic data through an effectiveness evaluation period (1year).

44. The method or use of clause 1, wherein the acute effectiveness rateis defined by pulmonary vein isolation touch-up by a focal catheteramong all targeted pulmonary veins.

45. The method or use of clause 1, wherein the predetermined clinicaleffectiveness rate is defined by 10% or less complication rates relatedto incidence of post-ablation symptomatic and asymptomatic cerebralemboli as compared to pre-ablation.

46. The method or use of clause 1, wherein the multi-electrodediagnostic catheter is configured for electrophysiological recording andstimulation of the atrial region of the heart and is used in conjunctionwith the multi-electrode radiofrequency balloon catheter.

47. A method or use to treat a plurality of patients for paroxysmalatrial fibrillation, the method or use comprising the steps of:

delivering a multi-electrode radiofrequency balloon catheter having aplurality of independently controllable electrodes for radiofrequencyablation and a multi-electrode diagnostic catheter to one or moretargeted pulmonary veins; and

ablating tissue of one or more targeted pulmonary veins with one or moreof the plurality of the electrodes independently controlledmulti-electrode radiofrequency balloon catheter;

diagnosing all targeted pulmonary veins using the multi-electrodediagnostic catheter; and

achieving a predetermined rate of adverse events based on use of themulti-electrode radiofrequency balloon catheter and the multi-electrodediagnostic catheter in the isolation of all targeted pulmonary veins,during and approximately 6 months after the use.

48. A method or use to treat a plurality of patients for paroxysmalatrial fibrillation, the method or use comprising the steps of:

evaluating a number and size of all targeted pulmonary veins and anatomyof the left atrial;

puncturing the transseptal;

selectively positioning a multi-electrode esophageal temperaturemonitoring device in the vasculature with respect to all targetedpulmonary veins;

selectively positioning a multi-electrode radiofrequency ballooncatheter in the vasculature with respect to all targeted pulmonaryveins, the multi-electrode radiofrequency balloon catheter having aplurality of independently controllable electrodes for radiofrequencyablation;

selectively positioning a multi-electrode diagnostic catheter in thevasculature with respect to all targeted pulmonary veins;

ablating tissue of all targeted pulmonary veins with one or more of theplurality of the electrodes independently controlled multi-electroderadiofrequency balloon catheter;

confirming isolation of all targeted pulmonary veins using themulti-electrode diagnostic catheter;

confirming existence of an entrance block in all targeted pulmonaryveins; and

achieving a predetermined clinical effectiveness and/or acuteeffectiveness of the method or use, based on the confirmed existence ofthe entrance block, regarding the isolation of all targeted pulmonaryveins following the method or use.

49. The method or use according to any of the preceding clauses, furthercomprising: mapping all targeted pulmonary veins using the diagnosticcatheter.

50. The method or use according to any of the preceding clauses, whereinexclusion criteria for the plurality of patients comprises at least oneof the following:

-   -   atrial fibrillation secondary to electrolyte imbalance, thyroid        disease, or reversible or non-cardiac cause;    -   previous surgical or catheter ablation for atrial fibrillation;    -   anticipated to receive ablation outside all targeted pulmonary        veins ostia and CTI region;    -   previously diagnosed with persistent, longstanding atrial        fibrillation and/or continuous atrial fibrillation >7 days,        or >48 hrs terminated by cardioversion;    -   any percutaneous coronary intervention (PCI) within the past 2        months;    -   valve repair or replacement and presence of a prosthetic valve;    -   any carotid stenting or endarterectomy;    -   coronary artery bypass grafting, cardiac surgery, valvular        cardiac surgical or percutaneous procedure within the past 6        months;    -   documented left atrium thrombus on baseline imaging;    -   LA antero posterior diameter greater than 50 mm;    -   any pulmonary vein with a diameter greater than or equal to 26        mm;    -   left ventricular ejection fraction less than 40%;    -   contraindication to anticoagulation;    -   history of blood clotting or bleeding abnormalities;    -   myocardial infarction within the past 2 months;    -   documented thromboembolic event within the past 12 months;    -   rheumatic heart disease;    -   awaiting cardiac transplantation or other cardiac surgery within        the next 12 months;    -   unstable angina;    -   acute illness or active systemic infection or sepsis;    -   diagnosed atrial myxoma or interatrial baffle or patch;    -   presence of implanted pacemaker, implantable cardioverter        defibrillator, tissue-embedded, or iron-containing metal        fragments;    -   significant pulmonary disease or any other disease or        malfunction of the lungs or respiratory system that produces        chronic symptoms;    -   significant congenital anomaly;    -   pregnancy or lactating;    -   enrollment in an investigational study evaluating another        device, biologic, or drug;    -   pulmonary vein stenosis;    -   presence of intramural thrombus, tumor or other abnormality that        precludes vascular access, or manipulation of the catheter;    -   presence of an IVC filter;    -   presence of a condition that precludes vascular access;    -   life expectancy or other disease processes likely to limit        survival to less than 12 months;    -   contraindication to use of contrast agents for MRI;    -   presence of iron-containing metal fragments in the patient; or    -   unresolved pre-existing neurological deficit.

51. The method or use of any previous clause, wherein themulti-electrode radiofrequency balloon catheter comprises:

a compliant balloon with a plurality of electrodes configured to deliverRF energy to tissue of all targeted pulmonary veins and sensetemperature at each electrode.

52. The method or use of clause 51, wherein the plurality of electrodesis oriented circularly to circumferentially contact with an ostia of thepulmonary vein.

53. The method or use of clause 51, further comprising using theplurality of electrodes for visualization, stimulation, recording, andablation.

54. The method or use of clause 51, wherein each electrode is configuredso an amount of power delivered to each electrode is controlledindependently.

55. The method or use of clause 51, wherein the multi-electroderadiofrequency balloon catheter further comprises a proximal handle, adistal tip, and a middle section disposed therebetween.

56. The method or use of clause 55, wherein the proximal handle is adeflection thumb knob allowing for unidirectional deflection, a balloonadvancement mechanism, and a luer fitting for balloon inflation andirrigation.

57. The method or use of clause 51, wherein the multi-electroderadiofrequency balloon catheter further comprises

a high-torque shaft configured to be rotated to facilitate accuratepositioning of the catheter tip to a desired; and

a unidirectional braided deflectable tip section.

58. The method or use of any preceding clause, further comprising:

controlling irrigation to the multi-electrode radiofrequency ballooncatheter with an irrigation pump.

59. The method or use of any preceding clause, further comprising:

administering uninterrupted anticoagulation therapy at least 1 monthprior to the procedure.

60. The method or use of any preceding clause, wherein if the patient isreceiving warfarin/coumadin therapy, the patient must have aninternational normalized ratio (INR) ≥2 for at least 3 weeks prior tothe procedure.

61. The method or use of any preceding clause, wherein if the patient isreceiving warfarin/coumadin therapy, the patient must be confirmed tohave an international normalized ratio (INR) ≥2 within 48 hourspre-procedure.

62. The method or use of any preceding clause, further comprising:continuing anticoagulation therapy prior to the procedure.

63. The method or use of any preceding clause, further comprising:

administering a transseptal puncture;

confirming an activated clotting time target of ≥350 sec. prior toinserting the multi-electrode radiofrequency balloon catheter into theleft atrium and maintaining throughout the procedure;

introducing the multi-electrode radiofrequency balloon catheter;

introducing of a multi-electrode circular diagnostic catheter;

ablating the pulmonary vein with the multi-electrode radiofrequencyballoon catheter;

determining in real time pulmonary vein isolation with themulti-electrode circular diagnostic catheter; and

confirming whether an entrance is blocked in the pulmonary vein.

64. The method or use of any preceding clause, wherein themulti-electrode circular diagnostic catheter comprises:

an elongated body having a longitudinal axis;

a distal assembly distal the elongated body, the distal assembly havinga helical form comprising a proximal loop and a distal loop, and ashape-memory support member extending through at least the proximalloop, the proximal loop and the distal loop being oriented obliquely atan angle relative to the longitudinal axis of the elongated body;

at least one irrigated ablation ring electrode mounted on the proximalloop;

a control handle proximal the elongated body; and

a contraction wire having a proximal end in the control handle and adistal end anchored in the proximal loop, the control handle including afirst control member configured to actuate the contraction wire tocontract the proximal loop,

wherein the proximal loop has a first flexibility and the distal loophas a second flexibility, and the second flexibility is greater than thefirst flexibility.

65. A method or use of treating a plurality of patients for paroxysmalatrial fibrillation by applying energy to tissue of a subject's heartproximate to an esophagus, phrenic nerve, or lung, the method or usecomprising the steps of:

achieving at least one of a predetermined clinical effectiveness andacute effectiveness of the procedure based on use of a multi-electroderadiofrequency balloon catheter and a multi-electrode diagnosticcatheter in the isolation of the one or more targeted pulmonary veinsby:

positioning an expandable member proximate to the left atrium, theexpandable member of the multi-electrode radiofrequency balloon catheterhaving a longitudinal axis and including a plurality of electrodesdisposed about the longitudinal axis, each electrode capable of beingenergized independently, the plurality of electrodes including a firstelectrode having a first radiopaque marker and a second electrode havinga second radiopaque marker different from the first radiopaque marker;

viewing an image of the expandable member as well as the first andsecond radiopaque markers in the left atrium;

determining an orientation of the first and second radiopaque markerswith respect to a

portion of the left atrium closest to the esophagus, phrenic nerve, orlung, of the subject;

moving one of the first and second radiopaque markers to a portion ofthe left atrium closest to the esophagus, phrenic nerve or lung;

energizing one or more electrodes indexed to the one of the radiopaquemarkers proximate the portion close to the esophagus, phrenic nerve, orlung, at a lower energization setting as compared to other electrodes tocreate a transmural lesion in the left atrium with little or no effectto adjacent anatomical structures; and

electrophysiologically recording and stimulating the atrial region ofthe tissue proximate to the esophagus, phrenic nerve, or lung using themulti-electrode diagnostic catheter.

66. A clinically effective device to treat atrial fibrillation in agroup of patients, the device comprising an end probe coupled to atubular member that extends along a longitudinal axis from a proximalportion to a distal portion, the end probe comprising:

a first expandable membrane coupled to the tubular member;

a plurality of electrodes disposed generally equiangularly about thelongitudinal axis on an outer surface of the first expandable membrane;

at least one wire connected each of the plurality of electrodes, the atleast one wire of each electrode extending from the first expandablemembrane toward the tubular member; and

a second expandable membrane that encapsulates a portion of the at leastone wire between the second expandable membrane and the first expandablemembrane; and

wherein the device is configured to achieve a predeterminedeffectiveness rate of pulmonary vein isolation in the group of patients.

67. A clinically effective device to administer a procedure for cardiacelectrophysiological ablation of pulmonary veins of the atria andtreatment of drug refractory recurrent symptomatic pulmonary atrialfibrillation, the device comprising:

an end probe coupled to a tubular member that extends along alongitudinal axis from a proximal portion to a distal portion, the endprobe comprising:

a first expandable membrane coupled to the tubular member;

a plurality of electrodes disposed generally equiangularly about thelongitudinal axis on an outer surface of the first expandable membrane;

at least one wire connected each of the plurality of electrodes, the atleast one wire of each electrode extending from the first expandablemembrane toward the tubular member; and

a second expandable membrane that encapsulates a portion of the at leastone wire between the second expandable membrane and the first expandablemembrane so that each of the plurality of electrodes is independentlycontrolled to achieve a predetermined effectiveness rate of pulmonaryvein isolation.

68. A clinically effective device to administer a procedure for cardiacelectrophysiological ablation of pulmonary veins of the atria andtreatment of drug refractory recurrent symptomatic pulmonary atrialfibrillation, the device comprising:

an end probe coupled to a tubular member that extends along alongitudinal axis from a proximal portion to a distal portion, the endprobe comprising:

a first expandable membrane coupled to the tubular member;

a plurality of electrodes disposed generally equiangularly about thelongitudinal axis on an outer surface of the first expandable membrane;

at least one wire connected each of the plurality of electrodes, the atleast one wire of each electrode extending from the first expandablemembrane toward the tubular member; and

a second expandable membrane that encapsulates a portion of the at leastone wire between the second expandable membrane and the first expandablemembrane so that each of the plurality of electrodes is independentlycontrolled to achieve pulmonary vein isolation and at least a 97% safetyendpoint within seven (7) days of successful pulmonary vein isolation.

69. A clinically effective device to administer a procedure for cardiacelectrophysiological ablation of pulmonary veins of the atria andtreatment of drug refractory recurrent symptomatic pulmonary atrialfibrillation, the device comprising:

an end probe coupled to a tubular member that extends along alongitudinal axis from a proximal portion to a distal portion, the endprobe comprising:

a first expandable membrane coupled to the tubular member;

a plurality of electrodes disposed generally equiangularly about thelongitudinal axis on an outer surface of the first expandable membrane;

at least one wire connected each of the plurality of electrodes, the atleast one wire of each electrode extending from the first expandablemembrane toward the tubular member; and

a second expandable membrane that encapsulates a portion of the at leastone wire between the second expandable membrane and the first expandablemembrane so that each of the plurality of electrodes is independentlycontrolled to achieve pulmonary vein isolation and at least a 90% safetyendpoint within seven (7) days of successful pulmonary vein isolation.

70. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate includes complication rates of 10% orless and is defined by existence or non-existence of asymptomaticcerebral embolic lesions at a discharge magnetic resonance imaging(MRI).

71. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate includes complication rates ofapproximately 0% and is defined by existence or non-existence ofesophageal injury erythema.

72. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate is approximately 100% and is defined byelectrically isolating all targeted pulmonary veins without use of afocal ablation catheter.

73. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate is defined by a freedom from documentedatrial fibrillation, atrial tachycardia, or atypical atrial flutterepisodes based on electrocardiographic data through an effectivenessevaluation period.

74. The device of Clause 73, wherein the effectiveness evaluation periodis approximately one year.

75. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate is defined by pulmonary vein isolationtouch-up by a focal catheter among all targeted pulmonary veins.

76. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate is defined by using focal catheterablation for non-PV triggers during the index procedure.

77. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate comprises a long-term effectivenessrate.

78. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate is defined by an average number ofRadio-Frequency applications per patient and Radio-Frequency timerequired to isolate all pulmonary veins.

79. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate is defined by an average number ofRadio-Frequency applications per vein and Radio-Frequency time requiredto isolate common pulmonary veins.

80. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate is defined by an average number ofRadio-Frequency applications per patient and Radio-Frequency timerequired to isolate common pulmonary veins.

81. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate is defined by determining incidence ofcomplication rates being 10% or less of post-ablation symptomatic andasymptomatic cerebral emboli as compared to pre-ablation.

82. The device of one of the preceding clauses, wherein thepredetermined effectiveness rate is defined by evaluating a presence ofemboli-associated neurological deficits by at least one of NIHSS and mRSassessments.

83. The device of any previous clause, wherein the end probe isconfigured for use in catheter-based cardiac electrophysiologicalmapping of the atria.

84. The device of any previous clause, wherein the end probe isconfigured for cardiac ablation.

85. The device of any previous clause, wherein the end probe comprises:the plurality of electrodes bonded to the first expandable membrane andconfigured to deliver Radio-Frequency energy to tissue of the pulmonaryvein and sense temperature at each electrode.

86. The device of any previous clause, wherein the plurality ofelectrodes is oriented circularly to circumferentially contact with anostia of the pulmonary vein.

87. The device of any previous clause, wherein the device is furtherconfigured for using the plurality of electrodes for visualization,stimulation, recording, and ablation.

88. The device of any previous clause, wherein each electrode isconfigured so an amount of power delivered to each electrode iscontrolled independently.

89. The device of any previous clause, wherein the end probe furthercomprises a proximal handle, a distal tip, and a middle section disposedtherebetween.

90. The device of any previous clause, wherein the proximal handle is adeflection thumb knob allowing for unidirectional deflection, a balloonadvancement mechanism, and a luer fitting for balloon inflation andirrigation.

91. The device of any previous clause, wherein the end probe furthercomprises

a high-torque shaft configured to be rotated to facilitate accuratepositioning of the catheter tip to a desired; and

a unidirectional braided deflectable tip section.

92. The device of any previous clause, wherein the end probe furthercomprises:

a first substrate disposed on the membrane, the first substrateincluding a first radiopaque marker of a first form disposed thereon;and

a second substrate disposed on the membrane, the second substrateincluding a second radiopaque marker of a second form disposed thereon,the second form being different from the first form.

93. The device of any previous clause, further comprising an irrigationpump to provide irrigation fluid to the first expandable membrane andout of the first expandable membrane.

94. The device of any preceding clause, wherein the effectivenessevaluation period is at least 91 days following a delivery of the endprobe to the pulmonary vein; and

ablation of tissue proximate the pulmonary vein with the end probe.

95. The device of any preceding clause, wherein the effectivenessevaluation period is less than or equal to one year following a deliveryof the end probe to the pulmonary vein; and

ablation of tissue proximate the pulmonary vein with the end probe.

96. The device of any previous clause, wherein the predetermined successrate is 60% for a population size of at least 40 patients.

97. The device of any previous clause, wherein a population size for thepredetermined success rate is at least 300 patients.

98. The device of any previous clause, wherein a population size for thepredetermined success rate is at least 200 patients.

99. The device of any previous clause, wherein a population size for thepredetermined success rate is at least 100 patients.

100. The device of any previous clause, wherein a population size forthe predetermined success rate is at least 50 patients.

101. The device of any previous clause, wherein the predeterminedsuccess rate is at least 60%.

102. The device of any previous clause, wherein the predeterminedsuccess rate is determined by evaluation of the patient 7 days followinga delivery of the end probe to the pulmonary vein and ablation of tissueproximate the pulmonary vein with the end probe.

103. The device of any previous clause, wherein the predeterminedsuccess rate is determined by evaluation of the patient 1 monthfollowing a delivery of the end probe to the pulmonary vein; andablation of tissue proximate the pulmonary vein with the end probe.

104. The device of any previous clause, wherein the predeterminedsuccess rate is determined by evaluation of the patient 6 monthsfollowing a delivery of the end probe to the pulmonary vein; andablation of tissue proximate the pulmonary vein with the end probe.

105. The device of any previous clause, wherein the predeterminedsuccess rate is determined by evaluation of the patient 12 monthsfollowing a delivery of the end probe to the pulmonary vein; andablation of tissue proximate the pulmonary vein with the end probe.

106. The device of any previous clause, wherein the predeterminedsuccess rate further comprises: confirmation of an entrance block in thepulmonary vein after at least one of adenosine and isoproterenolchallenge.

107. The device of any previous clause, wherein the patient suffering atleast one of the following events is deemed as unsuccessful pulmonaryvein isolation, including:

device or procedure related death;

atrio-esophageal fistula, myocardial infarction;

cardiac Tamponade/Perforation;

thromboembolism;

stroke/Cerebrovascular Accident (CVA);

transient Ischemic Attach (TIA);

phrenic Nerve Paralysis, Pulmonary Vein Stenosis;

pericarditis;

pulmonary Edema;

major Vascular Access Complication/Bleeding; and

hospitalization (initial or prolonged).

108. The device of any previous clause, wherein the patient suffering atleast one of the following events is deemed as unsuccessful pulmonaryvein isolation, comprising:

acute procedural failure;

repeat ablation or surgical treatment for AF/AT/Atypical (left-side) AFLafter the blanking period (after day 90 post index procedure);

DC cardioversion for AF/AT/Atypical (left-side) AFL, continuousAF/AT/AFL on a standard 12-lead ECG even if the recording is less than30 seconds in duration (after day 90 post index procedure);

a new Class I and/or Class III AAD is prescribed for AF duringeffectiveness evaluation period (day 91-365 post index procedure) orprescribed during the blanking period and continued past 90 days;

a previously failed Class I and/or Class III AAD (failed at or beforescreening) is taken for AF at a greater dose than the highestineffective historical dose during the effectiveness evaluation period;and

amiodarone is prescribed post procedure.

109. The device any previous clause, wherein the safety endpoint isdefined by a patient suffering a primary adverse event.

110. The device of any previous clause, wherein at least one risk factorfor the patient is selected from the group consisting of:

at least three (3) symptomatic episodes of atrial fibrillation that lastlasting ≥1 minute within six (6) months before the device;

at least one (1) atrial fibrillation episode electrocardiographicallydocumented within twelve (12) months prior to enrollment, wherebyelectrocardiographic documentation can include, but is not limited to,electrocardiogram (ECG), Holter monitor, or telemetry strip;

failing at least one (1) Class I or Class III AAD as evidenced byrecurrent symptomatic atrial fibrillation or intolerable side effects tothe AAD;

age 18-75 years;

secondary to electrolyte imbalance;

thyroid disease;

reversible or non-cardiac cause; and

previous surgical or catheter ablation for atrial fibrillation.

111. The device of any previous clause, wherein the patient has at leastone risk factor selected from the group consisting of:

Patients known to require ablation outside the PV ostia and CTI region;

Previously diagnosed with persistent or long-standing persistent atrialfibrillation and/or Continuous atrial fibrillation 7 days following thedevice procedure;

any percutaneous coronary intervention within the past 2 months;

repair or replacement or presence of a prosthetic valve;

any carotid stenting or endarterectomy within the past 6 months;

Coronary artery bypass grafting, cardiac surgery or valvular cardiacsurgical procedure within the past 6 months;

Documented left atrium thrombus within 1 day prior to the deviceprocedure;

left atrium antero posterior diameter >50 mm;

Left Ventricular Ejection Fraction <40%;

Contraindication to anticoagulation;

History of blood clotting or bleeding abnormalities;

Myocardial infarction within the past 2 months;

Documented thromboembolic event (including transient ischemic attack)within the past 12 months;

Rheumatic Heart Disease;

Uncontrolled heart failure or New York Heart Association (NYHA) functionclass III or IV;

Awaiting cardiac transplantation or other cardiac surgery within thenext 12 months;

Unstable angina;

Acute illness or active systemic infection or sepsis;

Diagnosed atrial myxoma or presence of an interatrial baffle or patch;

Presence of implanted pacemaker or implantable cardioverterdefibrillator (ICD);

Significant pulmonary disease or any other disease or malfunction of thelungs or respiratory system that produces chronic symptoms;

Significant congenital anomaly;

women who are pregnant;

enrollment in an investigational study evaluating another device,biologic, or drug;

known pulmonary vein stenosis;

presence of intramural thrombus, tumor or other abnormality thatprecludes vascular access, or manipulation of the catheter;

presence of an inferior vena cava filter;

presence of a condition that precludes vascular access;

life expectancy or other disease processes likely to limit survival toless than 12 months;

presenting contra-indication for the devices; and

patient on amiodarone at any time during the past 3 months prior toenrollment.

112. The device of any previous clause, wherein if the patient isreceiving warfarin/coumadin therapy, the patient must have aninternational normalized ratio ≥2 for at least 3 weeks prior to theprocedure.

113. The device of any previous clause, wherein if the patient isreceiving warfarin/coumadin therapy, the patient must be confirmed to be≥2 within 48 hours pre-procedure.

114. The device of any previous clause, wherein anticoagulation therapyis provided prior to the procedure.

115. The device of any previous clause, wherein an activated clottingtime of 350-400 seconds is targeted prior to insertion of the catheterand throughout the procedure.

116. The device of any previous clause, wherein an activated clottingtime levels are checked every 15-30 minutes during the procedure toensure an activated clotting time target of 350-400 seconds.

117. The device of any previous clause, wherein the multi-electrodecircular diagnostic catheter comprises:

an elongated body having a longitudinal axis;

a distal assembly distal the elongated body, the distal assembly havinga helical form comprising a proximal loop and a distal loop, and ashape-memory support member extending through at least the proximalloop, the proximal loop and the distal loop being oriented obliquely atan angle relative to the longitudinal axis of the elongated body;

at least one irrigated ablation ring electrode mounted on the proximalloop;

a control handle proximal the elongated body; and

a contraction wire having a proximal end in the control handle and adistal end anchored in the proximal loop, the control handle including afirst control member configured to actuate the contraction wire tocontract the proximal loop,

wherein the proximal loop has a first flexibility and the distal loophas a second flexibility, and the second flexibility is greater than thefirst flexibility.

118. A method or use of administering a procedure for treating atrialfibrillation, comprising:

delivering a multi-electrode radiofrequency balloon catheter to one ormore targeted pulmonary veins;

ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and

achieving a predetermined effectiveness rate of pulmonary veinisolation.

119. The method or use of clause 118, wherein the predeterminedeffectiveness rate includes complication rates of 10% or less and isdefined by existence of asymptomatic cerebral embolic lesions at adischarge magnetic resonance imaging (MRI).

120. The method or use of clause 118, wherein the predeterminedeffectiveness rate is defined by a freedom from documented atrialfibrillation, atrial tachycardia, or atypical atrial flutter episodesbased on electrocardiographic data through an effectiveness evaluationperiod.

121. The method or use of clause 120, wherein the effectivenessevaluation period is approximately one year.

122. The method or use of clause 118, wherein the predeterminedeffectiveness rate is defined by pulmonary vein isolation touch-up by afocal catheter among all targeted pulmonary veins.

123. The method or use of clause 118, wherein the predeterminedeffectiveness rate is defined by using focal catheter ablation fornon-PV triggers during the index procedure.

124. The method or use of clause 118, wherein the predeterminedeffectiveness rate comprises a long-term effectiveness rate.

125. The method or use of clause 118, wherein the predeterminedeffectiveness rate is defined by an average number of RF applicationsper patient and RF time required to isolate all pulmonary veins.

126. The method or use of clause 118, wherein the predeterminedeffectiveness rate is defined by an average number of RF applicationsper vein and RF time required to isolate common pulmonary veins.

127. The method or use of clause 118, wherein the predeterminedeffectiveness rate is defined by an average number of RF applicationsper patient and RF time required to isolate common pulmonary veins.

128. The method or use of clause 118, wherein the predeterminedeffectiveness rate is defined by determining incidence of complicationrates being 10% or less of post-ablation symptomatic and asymptomaticcerebral emboli as compared to pre-ablation.

129. The method or use of clause 118, wherein the predeterminedeffectiveness rate is defined by evaluating a presence ofemboli-associated neurological deficits by at least one of NIHSS and mRSassessments.

130. The method or use of any previous clause, wherein themulti-electrode radiofrequency balloon catheter is configured for use incatheter-based cardiac electrophysiological mapping of the atria.

131. The method or use of any previous clause, wherein themulti-electrode radiofrequency balloon catheter is configured forcardiac ablation.

132. The method or use of any previous clause, wherein themulti-electrode radiofrequency balloon catheter comprises:

a compliant balloon with a plurality of electrodes bonded configured todeliver RF energy to tissue of the pulmonary vein and sense temperatureat each electrode.

133. The method or use of clause 132, wherein the plurality ofelectrodes is oriented circularly to circumferentially contact with anostia of the pulmonary vein.

134. The method or use of clause 132, further comprising: using theplurality of electrodes for visualization, stimulation, recording, andablation.

135. The method or use of clause 132, wherein each electrode isconfigured so an amount of power delivered to each electrode iscontrolled independently.

136. The method or use of clause 132, wherein the multi-electroderadiofrequency balloon catheter further comprises a proximal handle, adistal tip, and a middle section disposed therebetween.

137. The method or use of clause 136, wherein the proximal handle is adeflection thumb knob allowing for unidirectional deflection, a balloonadvancement mechanism, and a luer fitting for balloon inflation andirrigation.

138. The method or use of clause 132, wherein the multi-electroderadiofrequency balloon catheter further comprises

a high-torque shaft configured to be rotated to facilitate accuratepositioning of the catheter tip to a desired; and

a unidirectional braided deflectable tip section.

139. The method or use of clause 132, wherein the balloon has amembrane, the balloon having a distal end and a proximal end defining alongitudinal axis, the multi-electrode radiofrequency balloon catheterfurther comprises:

a first substrate disposed on the membrane, the first substrateincluding a first radiopaque marker of a first form disposed thereon;and

a second substrate disposed on the membrane, the second substrateincluding a second radiopaque marker of a second form disposed thereon,the second form being different from the first form.

140. The method or use of any preceding clause, further comprising:

controlling irrigation to the multi-electrode radiofrequency ballooncatheter with an irrigation pump.

141. The method or use of any preceding clause, wherein theeffectiveness evaluation period is at least 91 days following:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

142. The method or use of any preceding clause, wherein theeffectiveness evaluation period is less than or equal to one yearfollowing:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

143. A method or use of administering a procedure for treating atrialfibrillation, comprising:

delivering a multi-electrode radiofrequency balloon catheter to apulmonary vein;

ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and

achieving a predetermined success rate of pulmonary vein isolation.

144. The method or use of clause 143, wherein the predetermined successrate is 60% for a population size of at least 40 patients.

145. The method or use of any previous clause, wherein a population sizefor the predetermined success rate is at least 300 patients.

146. The method or use of any previous clause, wherein a population sizefor the predetermined success rate is at least 200 patients.

147. The method or use of any previous clause, wherein a population sizefor the predetermined success rate is at least 100 patients.

148. The method or use of any previous clause, wherein a population sizefor the predetermined success rate is at least 50 patients.

149. The method or use of any previous clause, wherein the predeterminedsuccess rate is at least 60%.

150. The method or use of any previous clause, wherein the predeterminedsuccess rate is determined by evaluating the patient 7 days following:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

151. The method or use of any previous clause, wherein the predeterminedsuccess rate is determined by evaluating the patient 1 month following:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

152. The method or use of any previous clause, wherein the predeterminedsuccess rate is determined by evaluating the patient 6 months following:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

153. The method or use of any previous clause, wherein the predeterminedsuccess rate is determined by evaluating the patient 12 monthsfollowing:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

154. The method or use of any previous clause, wherein the predeterminedsuccess rate further comprises:

confirming an entrance block in the pulmonary vein after at least one ofadenosine and isoproterenol challenge.

155. The method or use of any previous clause, wherein the deliveringstep further comprises using a focal catheter.

156. The method or use of any preceding clause, wherein the patientsuffering at least one of the following events is deemed as unsuccessfulpulmonary vein isolation, including:

-   -   device or procedure related death;    -   atrio-esophageal fistula, myocardial infarction;    -   cardiac Tamponade/Perforation;    -   thromboembolism;    -   stroke/Cerebrovascular Accident (CVA);    -   transient Ischemic Attach (TIA);    -   phrenic Nerve Paralysis, Pulmonary Vein Stenosis;    -   pericarditis;    -   pulmonary Edema;    -   major Vascular Access Complication/Bleeding; and    -   hospitalization (initial or prolonged).

157. The method or use of any preceding clause, wherein the patientsuffering at least one of the following events is deemed as unsuccessfulpulmonary vein isolation, comprising:

-   -   acute procedural failure;    -   repeat ablation or surgical treatment for AF/AT/Atypical        (left-side) AFL after the blanking period (after day 90 post        index procedure);    -   DC cardioversion for AF/AT/Atypical (left-side) AFL, continuous        AF/AT/AFL on a standard 12-lead ECG even if the recording is        less than 30 seconds in duration (after day 90 post index        procedure);    -   a new Class I and/or Class III AAD is prescribed for AF during        effectiveness evaluation period (day 91-365 post index        procedure) or prescribed during the blanking period and        continued past 90 days;    -   a previously failed Class I and/or Class III AAD (failed at or        before screening) is taken for AF at a greater dose than the        highest ineffective historical dose during the effectiveness        evaluation period; and    -   amiodarone is prescribed post procedure.

158. A method or use for administering a procedure for cardiacelectrophysiological ablation of pulmonary veins of the atria andtreating drug refractory recurrent symptomatic pulmonary atrialfibrillation, comprising:

delivering a multi-electrode radiofrequency balloon catheter to apulmonary vein;

ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and

achieving a predetermined effectiveness rate of pulmonary veinisolation.

159. A method or use for administering a procedure for cardiacelectrophysiological ablation of pulmonary veins of the atria andtreating drug refractory recurrent symptomatic pulmonary atrialfibrillation, comprising:

delivering a multi-electrode radiofrequency balloon catheter to apulmonary vein;

ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and

achieving pulmonary vein isolation and at least a 97% safety endpointwithin seven (7) days of successful pulmonary vein isolation.

160. A method or use for administering a procedure for cardiacelectrophysiological ablation of pulmonary veins of the atria andtreating drug refractory recurrent symptomatic pulmonary atrialfibrillation, comprising:

delivering a multi-electrode radiofrequency balloon catheter to apulmonary vein;

ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and

achieving pulmonary vein isolation and at least a 90% safety endpointwithin seven (7) days of successful pulmonary vein isolation.

161. The method or use of any preceding clause, wherein the safetyendpoint is defined by a patient suffering a primary adverse event.

162. The method or use of any preceding clause, wherein at least onerisk factor for the patient is selected from the group consisting of:

-   -   at least three (3) symptomatic episodes of atrial fibrillation        that last lasting ≥1 minute within six (6) months before the        method or use;    -   at least one (1) atrial fibrillation episode        electrocardiographically documented within twelve (12) months        prior to enrollment. Electrocardiographic documentation can        include, but is not limited to, electrocardiogram (ECG), Holter        monitor, or telemetry strip;    -   failing at least one (1) Class I or Class III AAD as evidenced        by recurrent symptomatic atrial fibrillation or intolerable side        effects to the AAD;    -   age 18-75 years;    -   secondary to electrolyte imbalance;    -   thyroid disease;    -   reversible or non-cardiac cause; and    -   previous surgical or catheter ablation for atrial fibrillation.

163. The method or use of any preceding clause, wherein the patient hasat least one risk factor selected from the group consisting of:

-   -   Patients known to require ablation outside the PV ostia and CTI        region;    -   Previously diagnosed with persistent or long-standing persistent        atrial fibrillation and/or Continuous atrial fibrillation 7 days        following the method or use procedure;    -   any percutaneous coronary intervention within the past 2 months;    -   repair or replacement or presence of a prosthetic valve;    -   any carotid stenting or endarterectomy within the past 6 months;    -   Coronary artery bypass grafting, cardiac surgery or valvular        cardiac surgical procedure within the past 6 months;    -   Documented left atrium thrombus within 1 day prior to the method        or use procedure;    -   left atrium antero posterior diameter >50 mm;    -   Left Ventricular Ejection Fraction <40%;    -   Contraindication to anticoagulation;    -   History of blood clotting or bleeding abnormalities;    -   Myocardial infarction within the past 2 months;    -   Documented thromboembolic event (including transient ischemic        attack) within the past 12 months;    -   Rheumatic Heart Disease;    -   Uncontrolled heart failure or New York Heart Association (NYHA)        function class III or IV;    -   Awaiting cardiac transplantation or other cardiac surgery within        the next 12 months;    -   Unstable angina;    -   Acute illness or active systemic infection or sepsis;    -   Diagnosed atrial myxoma or presence of an interatrial baffle or        patch;    -   Presence of implanted pacemaker or implantable cardioverter        defibrillator (ICD);    -   Significant pulmonary disease or any other disease or        malfunction of the lungs or respiratory system that produces        chronic symptoms;    -   Significant congenital anomaly;    -   women who are pregnant;    -   enrollment in an investigational study evaluating another        device, biologic, or drug;    -   known pulmonary vein stenosis;    -   presence of intramural thrombus, tumor or other abnormality that        precludes vascular access, or manipulation of the catheter;    -   presence of an inferior vena cava filter;    -   presence of a condition that precludes vascular access;    -   life expectancy or other disease processes likely to limit        survival to less than 12 months;    -   presenting contra-indication for the devices; and    -   patient on amiodarone at any time during the past 3 months prior        to enrollment.

164. The method or use of any preceding clause, further comprising:

-   -   administering uninterrupted anticoagulation therapy at least 1        month prior to the procedure.

165. The method or use of any preceding clause, wherein if the patientis receiving warfarin/coumadin therapy, the patient must have aninternational normalized ratio >2 for at least 3 weeks prior to theprocedure.

166. The method or use of any preceding clause, wherein if the patientis receiving warfarin/coumadin therapy, the patient must be confirmed tobe ≥2 within 48 hours pre-procedure.

167. The method or use of any preceding clause, further comprising:continuing anticoagulation therapy prior to the procedure.

168. The method or use of any preceding clause, further comprising:targeting an activated clotting time of 350-400 seconds prior toinserting the catheter and throughout the procedure.

169. The method or use of any preceding clause, further comprising:checking an activated clotting time levels every 15-30 minutes duringthe procedure to ensure an activated clotting time target of 350-400seconds.

170. The method or use of any preceding clause, further comprising:

administering a transseptal puncture;

confirming an activated clotting time target of ≥350 sec. prior toinserting the multi-electrode radiofrequency balloon catheter into theleft atrium and maintaining throughout the procedure;

introducing the multi-electrode radiofrequency balloon catheter;

introducing of a multi-electrode circular diagnostic catheter;

ablating the pulmonary vein with the multi-electrode radiofrequencyballoon catheter;

determining in real time pulmonary vein isolation with themulti-electrode circular diagnostic catheter; and

confirming whether an entrance is blocked in the pulmonary vein.

171. The method or use of any preceding clause, wherein themulti-electrode circular diagnostic catheter comprises:

an elongated body having a longitudinal axis;

a distal assembly distal the elongated body, the distal assembly havinga helical form comprising a proximal loop and a distal loop, and ashape-memory support member extending through at least the proximalloop, the proximal loop and the distal loop being oriented obliquely atan angle relative to the longitudinal axis of the elongated body;

at least one irrigated ablation ring electrode mounted on the proximalloop;

a control handle proximal the elongated body; and

a contraction wire having a proximal end in the control handle and adistal end anchored in the proximal loop, the control handle including afirst control member configured to actuate the contraction wire tocontract the proximal loop,

wherein the proximal loop has a first flexibility and the distal loophas a second flexibility, and the second flexibility is greater than thefirst flexibility.

172. A method or use of pulmonary vein isolation by applying energy totissue of a subject's heart proximate to an esophagus, phrenic nerve, orlung, the method or use comprising the steps of:

achieving a predetermined effectiveness rate according to any of theprevious clauses by:

positioning an expandable member proximate to the left atrium, theexpandable member

having a longitudinal axis and including a plurality of electrodesdisposed about the longitudinal axis, each electrode capable of beingenergized independently, the plurality of electrodes including a firstelectrode having a first radiopaque marker and a second electrode havinga second radiopaque marker different from the first radiopaque marker;

viewing an image of the expandable member as well as the first andsecond radiopaque markers in the left atrium;

determining an orientation of the first and second radiopaque markerswith respect to a

portion of the left atrium closest to the esophagus, phrenic nerve, orlung, of the subject;

moving one of the first and second radiopaque markers to a portion ofthe left atrium closest to the esophagus, phrenic nerve or lung; and

energizing one or more electrodes indexed to the one of the radiopaquemarkers proximate the portion close to the esophagus, phrenic nerve, orlung, at a lower energization setting as compared to other electrodes tocreate a transmural lesion in the left atrium with little or no effectto adjacent anatomical structures.

173. Use of an independently controlled multi-electrode radiofrequencyballoon catheter to treat paroxysmal atrial fibrillation, comprising:

delivering a multi-electrode radiofrequency balloon catheter having aplurality of independently controllable electrodes for radiofrequencyablation and a multi-electrode diagnostic catheter to one or moretargeted pulmonary veins;

ablating tissue of the one or more targeted pulmonary veins with one ormore of the plurality of the electrodes independently controlledmulti-electrode radiofrequency balloon catheter;

diagnosing the one or more targeted pulmonary veins using themulti-electrode diagnostic catheter; and

achieving at least one of a predetermined clinical effectiveness andacute effectiveness of the multi-electrode radiofrequency ballooncatheter and the multi-electrode diagnostic catheter in the isolation ofthe one or more targeted pulmonary veins, during and approximately 3months after the ablating step.

174. Use according to Clause 173, wherein acute effectiveness is definedby confirming if there is an entrance block in all targeted pulmonaryveins after adenosine and/or isoproterenol challenge.

175. Use according to Clause 174, further comprising:

determining the acute effectiveness determined at approximately 3 monthsafter the ablating step; and

generating an estimated acute effectiveness at approximately 12 monthsafter the ablating step based on the acute effectiveness determined atapproximately 3 months.

176. Use according to Clause 175, wherein the estimated acuteeffectiveness at approximately 12 months is substantially similar to theacute effectiveness determined at approximately 3 months.

177. Use according to Clause 174, wherein the acute effectiveness isfurther defined by success greater than 90% for the plurality ofpatients.

178. Use according to Clause 174, wherein the acute effectiveness isfurther defined by success greater than 95% for the plurality ofpatients.

179. Use according to Clause 174, wherein a Type-1 error rate for powerthe acute effectiveness and the clinical effectiveness of all targetedveins are controlled at approximately a 5% level, use furthercomprising:

determining whether the ablating is clinically successful for theplurality of patients if both the acute effectiveness and the clinicaleffectiveness indications are controlled at approximately the 5% level.

180. Use according to Clause 174, wherein the acute effectiveness is atleast 80% for the plurality of patients being at least 80 patients.

181. Use according to Clause 174, wherein the acute effectiveness is atleast 80% for the plurality of patients being at least 130 patients.

182. Use according to Clause 174, wherein the acute effectiveness is atleast 80% for the plurality of patients being at least 180 patients.

183. Use according to Clause 174, wherein the acute effectiveness is atleast 80% for the plurality of patients being at least 230 patients.

184. Use according to Clause 174, wherein the acute effectiveness isfurther defined by confirming if there is an entrance block in alltargeted pulmonary veins after adenosine and/or isoproterenol challengeusing a focal ablation catheter.

185. Use according to Clause 174, wherein the acute effectiveness isfurther defined by confirming if there is an entrance block in alltargeted pulmonary veins after adenosine and/or isoproterenol challengewithout using a focal ablation catheter.

186. Use according to Clause 173, wherein the ablating is administeredon the plurality of patients diagnosed with symptomatic paroxysmalatrial fibrillation.

187. Use according to Clause 173, wherein the step of diagnosing furthercomprises:

electrophysiological mapping of the heart.

188. Use according to Clause 173, wherein the multi-electrode diagnosticcatheter further comprises a high torque shaft with a halo-shaped tipsection containing a plurality of pairs of electrodes visible underfluoroscopy.

189. Use according to Clause 173, wherein the plurality of patients isat least 80.

190. Use according to Clause 173, wherein the plurality of patients isat least 130.

191. Use according to Clause 173, wherein the plurality of patients isat least 180.

192. Use according to Clause 173, wherein the plurality of patients isat least 230.

193. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by ulceration being absent in the plurality ofpatients after the ablating.

194. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a complication rate of approximately 13% orfewer of the plurality of patients experiencing esophageal erythemaafter the ablating.

195. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a complication rate of approximately 25% orfewer of the plurality of patients experiencing new asymptomaticcerebral embolic lesions after the ablating.

196. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a complication rate of approximately 20% orfewer of the plurality of patients experiencing new asymptomaticcerebral embolic lesions after the ablating.

197. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a complication rate of approximately 5-9% orfewer of the plurality of patients experiencing a primary adverse eventby approximately 7 or more days after the ablating.

198. Use according to Clause 173, wherein inclusion criteria for theplurality of patients comprises:

a diagnosis with symptomatic paroxysmal atrial fibrillation; and

a patient capability to comply with uninterrupted per-protocolanticoagulation requirements.

199. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a total procedure time.

200. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a total ablation time.

201. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a total RF application time.

202. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a total dwell time of the multi-electroderadiofrequency balloon catheter.

203. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a total time to isolate all targetedpulmonary veins.

204. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a number and a total time of applications bythe multi-electrode radiofrequency balloon catheter per location of alltargeted pulmonary veins.

205. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a number and a total time of applications bythe multi-electrode radiofrequency balloon catheter per patient.

206. Use according to Clause 173, wherein the predetermined acuteeffectiveness is defined by a number and a total time of applications bythe multi-electrode radiofrequency balloon catheter per targeted vein.

207. Use according to Clause 173, wherein the multi-electroderadiofrequency balloon catheter comprises:

a compliant balloon with a plurality of electrodes bonded configured todeliver RF energy to tissue of the pulmonary vein and sense temperatureat each electrode.

208. Use according to Clause 173, wherein clinical effectiveness isdefined by an incidence of early onset of one or more adverse eventswithin a predetermined time of the use being implemented.

209. Use according to Clause 208, wherein the predetermined time is atleast 7 days.

210. Use according to Clause 208, wherein the one or more adverse eventscomprise: death, atrio-esophageal fistula, myocardial infarction,cardiac tamponade/perforation, thromboembolism, stroke, TIA (TransientIschemic Attack), phrenic nerve paralysis, pulmonary vein stenosis, andthe major vascular access bleeding.

211. Use according to Clause 208, wherein the one or more adverse eventscomprise: incidence of individual adverse events from a primarycomposite; incidence of serious adverse device effect; incidence ofserious adverse events within 7 days, at least 7 to 30 days, and atleast 30 days following the ablating; incidence of non-serious adverseevents; incidence of pre-and post-ablation asymptomatic and symptomaticcerebral emboli as determined by MRI evaluation; and frequency, anatomiclocation, and size (diameter and volume) of cerebral emboli by MRIevaluations at baseline, post-ablation and during follow-up.

212. Use according to Clause 208, wherein the one or more adverse eventsfor approximately 5-9% of the plurality of patients, the one or moreadverse events comprising:

NIHSS (National Institute of Health Stroke Scale) scores at baseline,post-ablation and during follow-up;

a summary of MoCA (Montreal Cognitive Assessment) and mRS (ModifiedRanking Scale) scores at baseline, 1 month and during further follow-up;a rate of hospitalization for cardiovascular events; a percentage (%) ofpulmonary vein isolation touch-up by focal catheter among the one ormore targeted veins;

a percentage (%) of subjects with use of focal catheter ablations fornon-PV triggers;

a percentage (%) of subjects with freedom from documented symptomaticatrial fibrillation (AF), atrial tachycardia (AT), or atypical (leftside) atrial flutter (AFL) episodes (episodes >30 seconds on arrhythmiamonitoring device from day 91 to 180);

a percentage (%) of subjects with freedom from documented atrialfibrillation (AF), atrial tachycardia (AT), or atypical (left side)atrial flutter (AFL);

one or more episodes that endure for 30 or more seconds on an arrhythmiamonitoring device from day 91 to 180 following the ablating; and

one or more procedural parameters including total procedure and ablationtime, balloon dwell time, RF application time, a number of RFapplications, fluoroscopy time and dose.

213. Use according to Clause 173, wherein the acute safety rate includescomplication rates of 10% or less and is defined by incidence ofasymptomatic cerebral embolic lesions at a discharge magnetic resonanceimaging (MRI).

214. Use according to Clause 173, wherein the acute effectiveness rateis 100% and is defined by electrically isolating all targeted pulmonaryveins without use of a focal ablation catheter.

215. Use according to Clause 173, wherein the acute effectiveness rateis defined by a freedom from documented atrial fibrillation, atrialtachycardia, or atypical atrial flutter episodes based onelectrocardiographic data through an effectiveness evaluation period (1year).

216. Use according to Clause 173, wherein the acute effectiveness rateis defined by pulmonary vein isolation touch-up by a focal catheteramong all targeted pulmonary veins.

217. Use according to Clause 173, wherein the predetermined clinicaleffectiveness rate is defined by 10% or less complication rates relatedto incidence of post-ablation symptomatic and asymptomatic cerebralemboli as compared to pre-ablation.

218. Use according to Clause 173, wherein the multi-electrode diagnosticcatheter is configured for electrophysiological recording andstimulation of the atrial region of the heart and is used in conjunctionwith the multi-electrode radiofrequency balloon catheter.

219. Use of an independently controlled multi-electrode radiofrequencyballoon catheter to treat a plurality of patients for paroxysmal atrialfibrillation, comprising:

delivering a multi-electrode radiofrequency balloon catheter having aplurality of independently controllable electrodes for radiofrequencyablation and a multi-electrode diagnostic catheter to one or moretargeted pulmonary veins; and

ablating tissue of one or more targeted pulmonary veins with one or moreof the plurality of the electrodes independently controlledmulti-electrode radiofrequency balloon catheter;

diagnosing all targeted pulmonary veins using the multi-electrodediagnostic catheter; and

achieving a predetermined rate of adverse events based on use of themulti-electrode radiofrequency balloon catheter and the multi-electrodediagnostic catheter in the isolation of all targeted pulmonary veins,during and approximately 6 months after use.

220. Use of an independently controlled multi-electrode radiofrequencyballoon catheter to treat a plurality of patients for paroxysmal atrialfibrillation, comprising:

evaluating a number and size of all targeted pulmonary veins and anatomyof the left atrial;

puncturing the transseptal;

selectively positioning a multi-electrode esophageal temperaturemonitoring device in the vasculature with respect to all targetedpulmonary veins;

selectively positioning a multi-electrode radiofrequency ballooncatheter in the vasculature with respect to all targeted pulmonaryveins, the multi-electrode radiofrequency balloon catheter having aplurality of independently controllable electrodes for radiofrequencyablation;

selectively positioning a multi-electrode diagnostic catheter in thevasculature with respect to all targeted pulmonary veins;

ablating tissue of all targeted pulmonary veins with one or more of theplurality of the electrodes independently controlled multi-electroderadiofrequency balloon catheter;

confirming isolation of all targeted pulmonary veins using themulti-electrode diagnostic catheter;

confirming existence of an entrance block in all targeted pulmonaryveins;

achieving a predetermined clinical effectiveness and/or acuteeffectiveness of the method or use, based on the confirmed existence ofthe entrance block, regarding the isolation of all targeted pulmonaryveins following the method or use.

221. Use of any previous clause, further comprising: mapping alltargeted pulmonary veins using the diagnostic catheter.

222. Use of any previous clause, wherein exclusion criteria for theplurality of patients comprises at least one of the following:

-   -   atrial fibrillation secondary to electrolyte imbalance, thyroid        disease, or reversible or non-cardiac cause;    -   previous surgical or catheter ablation for atrial fibrillation;    -   anticipated to receive ablation outside all targeted pulmonary        veins ostia and CTI region;    -   previously diagnosed with persistent, longstanding atrial        fibrillation and/or continuous atrial fibrillation >7 days,        or >48 hrs terminated by cardioversion;    -   any percutaneous coronary intervention (PCI) within the past 2        months;    -   valve repair or replacement and presence of a prosthetic valve;    -   any carotid stenting or endarterectomy;    -   coronary artery bypass grafting, cardiac surgery, valvular        cardiac surgical or percutaneous procedure within the past 6        months;    -   documented left atrium thrombus on baseline imaging;    -   LA antero posterior diameter greater than 50 mm;    -   any pulmonary vein with a diameter greater than or equal to 26        mm;    -   left ventricular ejection fraction less than 40%;    -   contraindication to anticoagulation;    -   history of blood clotting or bleeding abnormalities;    -   myocardial infarction within the past 2 months;    -   documented thromboembolic event within the past 12 months;    -   rheumatic heart disease;    -   awaiting cardiac transplantation or other cardiac surgery within        the next 12 months;    -   unstable angina;    -   acute illness or active systemic infection or sepsis;    -   diagnosed atrial myxoma or interatrial baffle or patch;    -   presence of implanted pacemaker, implantable cardioverter        defibrillator, tissue-embedded, or iron-containing metal        fragments;    -   significant pulmonary disease or any other disease or        malfunction of the lungs or respiratory system that produces        chronic symptoms;    -   significant congenital anomaly;    -   pregnancy or lactating;    -   enrollment in an investigational study evaluating another        device, biologic, or drug;    -   pulmonary vein stenosis;    -   presence of intramural thrombus, tumor or other abnormality that        precludes vascular access, or manipulation of the catheter;    -   presence of an IVC filter;    -   presence of a condition that precludes vascular access;    -   life expectancy or other disease processes likely to limit        survival to less than 12 months;    -   contraindication to use of contrast agents for MRI;    -   presence of iron-containing metal fragments in the patient; or    -   unresolved pre-existing neurological deficit.

223. Use of any previous clause, wherein the multi-electroderadiofrequency balloon catheter comprises:

-   -   a compliant balloon with a plurality of electrodes configured to        deliver RF energy to tissue of all targeted pulmonary veins and        sense temperature at each electrode.

224. Use according to Clause 223, wherein the plurality of electrodes isoriented circularly to circumferentially contact with an ostia of thepulmonary vein.

225. Use according to Clause 223, further comprising using the pluralityof electrodes for visualization, stimulation, recording, and ablation.

226. Use according to Clause 223, wherein each electrode is configuredso an amount of power delivered to each electrode is controlledindependently.

227. Use according to Clause 223, wherein the multi-electroderadiofrequency balloon catheter further comprises a proximal handle, adistal tip, and a middle section disposed therebetween.

228. Use according to Clause 227, wherein the proximal handle is adeflection thumb knob allowing for unidirectional deflection, a balloonadvancement mechanism, and a luer fitting for balloon inflation andirrigation.

229. Use according to Clause 223, wherein the multi-electroderadiofrequency balloon catheter further comprises

a high-torque shaft configured to be rotated to facilitate accuratepositioning of the catheter tip to a desired; and

a unidirectional braided deflectable tip section.

230. Use of any previous clause, further comprising:

controlling irrigation to the multi-electrode radiofrequency ballooncatheter with an irrigation pump.

231. Use of any previous clause, further comprising:

administering uninterrupted anticoagulation therapy at least 1 monthprior to the procedure.

232. Use of any previous clause, wherein if the patient is receivingwarfarin/coumadin therapy, the patient must have an internationalnormalized ratio (INR) ≥2 for at least 3 weeks prior to the procedure.

233. Use of any previous clause, wherein if the patient is receivingwarfarin/coumadin therapy, the patient must be confirmed to have aninternational normalized ratio (INR) ≥2 within 48 hours pre-procedure.

234. Use of any previous clause, further comprising: continuinganticoagulation therapy prior to the procedure.

235. Use of any previous clause, further comprising:

administering a transseptal puncture;

confirming an activated clotting time target of ≥350 sec. prior toinserting the multi-electrode radiofrequency balloon catheter into theleft atrium and maintaining throughout the procedure;

introducing the multi-electrode radiofrequency balloon catheter;

introducing of a multi-electrode circular diagnostic catheter;

ablating the pulmonary vein with the multi-electrode radiofrequencyballoon catheter;

determining in real time pulmonary vein isolation with themulti-electrode circular diagnostic catheter; and

confirming whether an entrance is blocked in the pulmonary vein.

236. Use of any previous clause, wherein the multi-electrode circulardiagnostic catheter comprises:

an elongated body having a longitudinal axis;

a distal assembly distal the elongated body, the distal assembly havinga helical form comprising a proximal loop and a distal loop, and ashape-memory support member extending through at least the proximalloop, the proximal loop and the distal loop being oriented obliquely atan angle relative to the longitudinal axis of the elongated body;

at least one irrigated ablation ring electrode mounted on the proximalloop;

a control handle proximal the elongated body; and

a contraction wire having a proximal end in the control handle and adistal end anchored in the proximal loop, the control handle including afirst control member configured to actuate the contraction wire tocontract the proximal loop,

wherein the proximal loop has a first flexibility and the distal loophas a second flexibility, and the second flexibility is greater than thefirst flexibility.

237. Use of an independently controlled multi-electrode radiofrequencyballoon catheter to treat a plurality of patients for paroxysmal atrialfibrillation by applying energy to tissue of a subject's heart proximateto an esophagus, phrenic nerve, or lung, comprising:

achieving at least one of a predetermined clinical effectiveness andacute effectiveness of the procedure based on use of the multi-electroderadiofrequency balloon catheter and a multi-electrode diagnosticcatheter in the isolation of the one or more targeted pulmonary veinsby:

positioning an expandable member proximate to the left atrium, theexpandable member of the multi-electrode radiofrequency balloon catheterhaving a longitudinal axis and including a plurality of electrodesdisposed about the longitudinal axis, each electrode capable of beingenergized independently, the plurality of electrodes including a firstelectrode having a first radiopaque marker and a second electrode havinga second radiopaque marker different from the first radiopaque marker;

viewing an image of the expandable member as well as the first andsecond radiopaque markers in the left atrium;

determining an orientation of the first and second radiopaque markerswith respect to a

portion of the left atrium closest to the esophagus, phrenic nerve, orlung, of the subject;

moving one of the first and second radiopaque markers to a portion ofthe left atrium closest to the esophagus, phrenic nerve or lung;

energizing one or more electrodes indexed to the one of the radiopaquemarkers proximate the portion close to the esophagus, phrenic nerve, orlung, at a lower energization setting as compared to other electrodes tocreate a transmural lesion in the left atrium with little or no effectto adjacent anatomical structures; and

electrophysiologically recording and stimulating the atrial region ofthe tissue proximate to the esophagus, phrenic nerve, or lung using themulti-electrode diagnostic catheter.

238. Use of administering an independently controlled multi-electroderadiofrequency balloon catheter for a procedure for atrial fibrillation,comprising:

delivering a multi-electrode radiofrequency balloon catheter to one ormore targeted pulmonary veins;

ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and

achieving a predetermined effectiveness rate of pulmonary veinisolation.

239. Use according to Clause 238, wherein the predeterminedeffectiveness rate includes complication rates of 10% or less and isdefined by existence of asymptomatic cerebral embolic lesions at adischarge magnetic resonance imaging (MRI).

240. Use according to Clause 238, wherein the predeterminedeffectiveness rate is defined by a freedom from documented atrialfibrillation, atrial tachycardia, or atypical atrial flutter episodesbased on electrocardiographic data through an effectiveness evaluationperiod.

241. Use according to Clause 240, wherein the effectiveness evaluationperiod is approximately one year.

242. Use according to Clause 238, wherein the predeterminedeffectiveness rate is defined by pulmonary vein isolation touch-up by afocal catheter among all targeted pulmonary veins.

243. Use according to Clause 238, wherein the predeterminedeffectiveness rate is defined by using focal catheter ablation fornon-PV triggers during the index procedure.

244. Use according to Clause 238, wherein the predeterminedeffectiveness rate comprises a long term effectiveness rate.

245. Use according to Clause 238, wherein the predeterminedeffectiveness rate is defined by an average number of RF applicationsper patient and RF time required to isolate all pulmonary veins.

246. Use according to Clause 238, wherein the predeterminedeffectiveness rate is defined by an average number of RF applicationsper vein and RF time required to isolate common pulmonary veins.

247. Use according to Clause 238, wherein the predeterminedeffectiveness rate is defined by an average number of RF applicationsper patient and RF time required to isolate common pulmonary veins.

248. Use according to Clause 238, wherein the predeterminedeffectiveness rate is defined by determining incidence of complicationrates being 10% or less of post-ablation symptomatic and asymptomaticcerebral emboli as compared to pre-ablation.

249. Use according to Clause 238, wherein the predeterminedeffectiveness rate is defined by evaluating a presence ofemboli-associated neurological deficits by at least one of NIHSS and mRSassessments.

250. Use of any previous clause, wherein the multi-electroderadiofrequency balloon catheter is configured for use in catheter-basedcardiac electrophysiological mapping of the atria.

251. Use of any previous clause, wherein the multi-electroderadiofrequency balloon catheter is configured for cardiac ablation.

252. Use of any previous clause, wherein the multi-electroderadiofrequency balloon catheter comprises:

a compliant balloon with a plurality of electrodes bonded configured todeliver RF energy to tissue of the pulmonary vein and sense temperatureat each electrode.

253. Use according to Clause 252, wherein the plurality of electrodes isoriented circularly to circumferentially contact with an ostia of thepulmonary vein.

254. Use according to Clause 252, further comprising: using theplurality of electrodes for visualization, stimulation, recording, andablation.

255. Use according to Clause 252, wherein each electrode is configuredso an amount of power delivered to each electrode is controlledindependently.

256. Use according to Clause 252, wherein the multi-electroderadiofrequency balloon catheter further comprises a proximal handle, adistal tip, and a middle section disposed therebetween.

257. Use according to Clause 256, wherein the proximal handle is adeflection thumb knob allowing for unidirectional deflection, a balloonadvancement mechanism, and a luer fitting for balloon inflation andirrigation.

258. Use according to Clause 252, wherein the multi-electroderadiofrequency balloon catheter further comprises

a high-torque shaft configured to be rotated to facilitate accuratepositioning of the catheter tip to a desired; and

a unidirectional braided deflectable tip section.

259. Use according to Clause 252, wherein the balloon has a membrane,the balloon having a distal end and a proximal end defining alongitudinal axis, the multi-electrode radiofrequency balloon catheterfurther comprises:

a first substrate disposed on the membrane, the first substrateincluding a first radiopaque marker of a first form disposed thereon;and

a second substrate disposed on the membrane, the second substrateincluding a second radiopaque marker of a second form disposed thereon,the second form being different from the first form.

260. Use of any previous clause, further comprising:

controlling irrigation to the multi-electrode radiofrequency ballooncatheter with an irrigation pump.

261. Use of any previous clause, wherein the effectiveness evaluationperiod is at least 91 days following:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

262. Use of any previous clause, wherein the effectiveness evaluationperiod is less than or equal to one year following:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

263. Use of administering an independently controlled multi-electroderadiofrequency balloon catheter for a procedure for atrial fibrillation,comprising:

delivering a multi-electrode radiofrequency balloon catheter to apulmonary vein;

ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and

achieving a predetermined success rate of pulmonary vein isolation.

264. Use according to Clause 263, wherein the predetermined success rateis 60% for a population size of at least 40 patients.

265. Use of any previous clause, wherein a population size for thepredetermined success rate is at least 300 patients.

266. Use of any previous clause, wherein a population size for thepredetermined success rate is at least 200 patients.

267. Use of any previous clause, wherein a population size for thepredetermined success rate is at least 100 patients.

268. Use of any previous clause, wherein a population size for thepredetermined success rate is at least 50 patients.

269. Use of any previous clause, wherein the predetermined success rateis at least 60%.

270. Use of any previous clause, wherein the predetermined success rateis determined by evaluating the patient 7 days following:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

271. Use of any previous clause, wherein the predetermined success rateis determined by evaluating the patient 1 month following:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

272. Use of any previous clause, wherein the predetermined success rateis determined by evaluating the patient 6 months following:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

273. Use of any previous clause, wherein the predetermined success rateis determined by evaluating the patient 12 months following:

the delivering the multi-electrode radiofrequency balloon catheter tothe pulmonary vein; and

the ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter.

274. Use of any previous clause, wherein the predetermined success ratefurther comprises:

confirming an entrance block in the pulmonary vein after at least one ofadenosine and isoproterenol challenge.

275. Use of any previous clause, wherein the delivering step furthercomprises using a focal catheter.

276. Use of any previous clause, wherein the patient suffering at leastone of the following events is deemed as unsuccessful pulmonary veinisolation, including:

-   -   device or procedure related death;    -   atrio-esophageal fistula, myocardial infarction;    -   cardiac Tamponade/Perforation;    -   thromboembolism;    -   stroke/Cerebrovascular Accident (CVA);    -   transient Ischemic Attach (TIA);    -   phrenic Nerve Paralysis, Pulmonary Vein Stenosis;    -   pericarditis;    -   pulmonary Edema;    -   major Vascular Access Complication/Bleeding; and    -   hospitalization (initial or prolonged).

277. Use of any previous clause, wherein the patient suffering at leastone of the following events is deemed as unsuccessful pulmonary veinisolation, comprising:

-   -   acute procedural failure;    -   repeat ablation or surgical treatment for AF/AT/Atypical        (left-side) AFL after the blanking period (after day 90 post        index procedure);    -   DC cardioversion for AF/AT/Atypical (left-side) AFL, continuous        AF/AT/AFL on a standard 12-lead ECG even if the recording is        less than 30 seconds in duration (after day 90 post index        procedure);    -   a new Class I and/or Class III AAD is prescribed for AF during        effectiveness evaluation period (day 91-365 post index        procedure) or prescribed during the blanking period and        continued past 90 days;    -   a previously failed Class I and/or Class III AAD (failed at or        before screening) is taken for AF at a greater dose than the        highest ineffective historical dose during the effectiveness        evaluation period; and    -   amiodarone is prescribed post procedure.

278. Use of administering an independently controlled multi-electroderadiofrequency balloon catheter for a procedure for cardiacelectrophysiological ablation of pulmonary veins of the atria andtreating drug refractory recurrent symptomatic pulmonary atrialfibrillation, comprising:

delivering a multi-electrode radiofrequency balloon catheter to apulmonary vein;

ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and

achieving a predetermined effectiveness rate of pulmonary veinisolation.

279. Use of administering an independently controlled multi-electroderadiofrequency balloon catheter for a procedure for cardiacelectrophysiological ablation of pulmonary veins of the atria and drugrefractory recurrent symptomatic pulmonary atrial fibrillation,comprising:

delivering a multi-electrode radiofrequency balloon catheter to apulmonary vein;

ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and

achieving pulmonary vein isolation and at least a 97% safety endpointwithin seven (7) days of successful pulmonary vein isolation.

280. Use of administering an independently controlled multi-electroderadiofrequency balloon catheter for a procedure for drug refractoryrecurrent symptomatic pulmonary atrial fibrillation, comprising:

delivering a multi-electrode radiofrequency balloon catheter to apulmonary vein;

ablating tissue of the pulmonary vein using the multi-electroderadiofrequency balloon catheter; and

achieving pulmonary vein isolation and at least a 90% safety endpointwithin seven (7) days of successful pulmonary vein isolation.

281. Use of any previous clause, wherein the safety endpoint is definedby a patient suffering a primary adverse event.

282. Use of any previous clause, wherein at least one risk factor forthe patient is selected from the group consisting of:

-   -   at least three (3) symptomatic episodes of atrial fibrillation        that last lasting ≥1 minute within six (6) months before the        method or use;    -   at least one (1) atrial fibrillation episode        electrocardiographically documented within twelve (12) months        prior to enrollment. Electrocardiographic documentation can        include, but is not limited to, electrocardiogram (ECG), Holter        monitor, or telemetry strip;    -   failing at least one (1) Class I or Class III AAD as evidenced        by recurrent symptomatic atrial fibrillation or intolerable side        effects to the AAD;    -   age 18-75 years;    -   secondary to electrolyte imbalance;    -   thyroid disease;    -   reversible or non-cardiac cause; and    -   previous surgical or catheter ablation for atrial fibrillation.

283. Use of any previous clause, wherein the patient has at least onerisk factor selected from the group consisting of:

-   -   Patients known to require ablation outside the PV ostia and CTI        region;    -   Previously diagnosed with persistent or long-standing persistent        atrial fibrillation and/or Continuous atrial fibrillation 7 days        following the method or use procedure;    -   any percutaneous coronary intervention within the past 2 months;    -   repair or replacement or presence of a prosthetic valve;    -   any carotid stenting or endarterectomy within the past 6 months;    -   Coronary artery bypass grafting, cardiac surgery or valvular        cardiac surgical procedure within the past 6 months;    -   Documented left atrium thrombus within 1 day prior to the method        or use procedure;    -   left atrium antero posterior diameter >50 mm;    -   Left Ventricular Ejection Fraction <40%;    -   Contraindication to anticoagulation;    -   History of blood clotting or bleeding abnormalities;    -   Myocardial infarction within the past 2 months;    -   Documented thromboembolic event (including transient ischemic        attack) within the past 12 months;    -   Rheumatic Heart Disease;    -   Uncontrolled heart failure or New York Heart Association (NYHA)        function class III or IV;    -   Awaiting cardiac transplantation or other cardiac surgery within        the next 12 months;    -   Unstable angina;    -   Acute illness or active systemic infection or sepsis;    -   Diagnosed atrial myxoma or presence of an interatrial baffle or        patch;    -   Presence of implanted pacemaker or implantable cardioverter        defibrillator (ICD);    -   Significant pulmonary disease or any other disease or        malfunction of the lungs or respiratory system that produces        chronic symptoms;    -   Significant congenital anomaly;    -   women who are pregnant;    -   enrollment in an investigational study evaluating another        device, biologic, or drug;    -   known pulmonary vein stenosis;    -   presence of intramural thrombus, tumor or other abnormality that        precludes vascular access, or manipulation of the catheter;    -   presence of an inferior vena cava filter;    -   presence of a condition that precludes vascular access;    -   life expectancy or other disease processes likely to limit        survival to less than 12 months;    -   presenting contra-indication for the devices; and    -   patient on amiodarone at any time during the past 3 months prior        to enrollment.

284. Use of any previous clause, further comprising:

administering uninterrupted anticoagulation therapy at least 1 monthprior to the procedure.

285. Use of any previous clause, wherein if the patient is receivingwarfarin/coumadin therapy, the patient must have an internationalnormalized ratio ≥2 for at least 3 weeks prior to the procedure.

286. Use of any previous clause, wherein if the patient is receivingwarfarin/coumadin therapy, the patient must be confirmed to be ≥2 within48 hours pre-procedure.

287. Use of any previous clause, further comprising: continuinganticoagulation therapy prior to the procedure.

288. Use of any previous clause, further comprising: targeting anactivated clotting time of 350-400 seconds prior to inserting thecatheter and throughout the procedure.

289. Use of any previous clause, further comprising: checking anactivated clotting time levels every 15-30 minutes during the procedureto ensure an activated clotting time target of 350-400 seconds.

290. Use of any previous clause, further comprising:

administering a transseptal puncture;

confirming an activated clotting time target of ≥350 sec. prior toinserting the multi-electrode radiofrequency balloon catheter into theleft atrium and maintaining throughout the procedure;

introducing the multi-electrode radiofrequency balloon catheter;

introducing of a multi-electrode circular diagnostic catheter;

ablating the pulmonary vein with the multi-electrode radiofrequencyballoon catheter;

determining in real time pulmonary vein isolation with themulti-electrode circular diagnostic catheter; and

confirming whether an entrance is blocked in the pulmonary vein.

291. Use of any previous clause, wherein the multi-electrode circulardiagnostic catheter comprises:

an elongated body having a longitudinal axis;

a distal assembly distal the elongated body, the distal assembly havinga helical form comprising a proximal loop and a distal loop, and ashape-memory support member extending through at least the proximalloop, the proximal loop and the distal loop being oriented obliquely atan angle relative to the longitudinal axis of the elongated body;

at least one irrigated ablation ring electrode mounted on the proximalloop;

a control handle proximal the elongated body; and

a contraction wire having a proximal end in the control handle and adistal end anchored in the proximal loop, the control handle including afirst control member configured to actuate the contraction wire tocontract the proximal loop,

wherein the proximal loop has a first flexibility and the distal loophas a second flexibility, and the second flexibility is greater than thefirst flexibility.

292. Use of administering an independently controlled multi-electroderadiofrequency balloon catheter for a procedure for pulmonary veinisolation by applying energy to tissue of a subject's heart proximate toan esophagus, phrenic nerve, or lung, comprising:

achieving a predetermined effectiveness rate according to any of theprevious clauses by:

positioning an expandable member proximate to the left atrium, theexpandable member

having a longitudinal axis and including a plurality of electrodesdisposed about the longitudinal axis, each electrode capable of beingenergized independently, the plurality of electrodes including a firstelectrode having a first radiopaque marker and a second electrode havinga second radiopaque marker different from the first radiopaque marker;

viewing an image of the expandable member as well as the first andsecond radiopaque markers in the left atrium;

determining an orientation of the first and second radiopaque markerswith respect to a

portion of the left atrium closest to the esophagus, phrenic nerve, orlung, of the subject;

moving one of the first and second radiopaque markers to a portion ofthe left atrium closest to the esophagus, phrenic nerve or lung; and

energizing one or more electrodes indexed to the one of the radiopaquemarkers proximate the portion close to the esophagus, phrenic nerve, orlung, at a lower energization setting as compared to other electrodes tocreate a transmural lesion in the left atrium with little or no effectto adjacent anatomical structures.

What is claimed is:
 1. A clinically effective device to treat atrialfibrillation in a group of patients, the device comprising an end probecoupled to a tubular member that extends along a longitudinal axis froma proximal portion to a distal portion, the end probe comprising: afirst expandable membrane coupled to the tubular member; a plurality ofelectrodes disposed generally equiangularly about the longitudinal axison an outer surface of the first expandable membrane; at least one wireconnected each of the plurality of electrodes, the at least one wire ofeach electrode extending from the first expandable membrane toward thetubular member; and a second expandable membrane that encapsulates aportion of the at least one wire between the second expandable membraneand the first expandable membrane; wherein the device is configured toachieve a predetermined effectiveness rate of pulmonary vein isolationin the group of patients, and wherein acute effectiveness is defined byconfirming if there is an entrance block in all targeted pulmonary veinsafter adenosine and/or isoproterenol challenge, the acute effectivenessbeing defined by success greater than approximately 80% for the group ofpatients.
 2. The device of claim 1, wherein the predeterminedeffectiveness rate includes complication rates of 10% or less and isdefined by existence or non-existence of asymptomatic cerebral emboliclesions at a discharge magnetic resonance imaging (MRI).
 3. The deviceof claim 1, wherein the predetermined effectiveness rate includescomplication rates of approximately 0% and is defined by existence ornon-existence of esophageal injury erythema.
 4. The device of claim 1,wherein the predetermined effectiveness rate is approximately 100% andis defined by electrically isolating all targeted pulmonary veinswithout use of a focal ablation catheter.
 5. The device of claim 1,wherein the predetermined effectiveness rate is defined by a freedomfrom documented atrial fibrillation, atrial tachycardia, or atypicalatrial flutter episodes based on electrocardiographic data through aneffectiveness evaluation period.
 6. The device of claim 5, wherein theeffectiveness evaluation period is approximately one year.
 7. The deviceof claim 1, wherein the predetermined effectiveness rate is defined bypulmonary vein isolation touch-up by a focal catheter among all targetedpulmonary veins.
 8. The device of claim 1, wherein the predeterminedeffectiveness rate is defined by using focal catheter ablation fornon-PV triggers during an index procedure.
 9. The device of claim 1,wherein the predetermined effectiveness rate comprises a long-termeffectiveness rate.
 110. The device of claim 1, wherein thepredetermined effectiveness rate is defined by an average number ofRadio-Frequency applications per patient and Radio-Frequency timerequired to isolate all pulmonary veins.
 11. The device of claim 1,wherein the predetermined effectiveness rate is defined by an averagenumber of Radio-Frequency applications per vein and Radio-Frequency timerequired to isolate common pulmonary veins.
 12. The device of claim 1,wherein the predetermined effectiveness rate is defined by an averagenumber of Radio-Frequency applications per patient and Radio-Frequencytime required to isolate common pulmonary veins.
 13. The device of claim1, wherein the predetermined effectiveness rate is defined bydetermining incidence of complication rates being 10% or less ofpost-ablation symptomatic and asymptomatic cerebral emboli as comparedto pre-ablation.
 14. The device of claim 1, wherein the predeterminedeffectiveness rate is defined by evaluating a presence ofemboli-associated neurological deficits by at least one of NIHSS and mRSassessments.
 15. The device of claim 1, wherein the end probe isconfigured for use in catheter-based cardiac electrophysiologicalmapping of the atria.
 16. The device of claim 1, wherein the end probeis configured for cardiac ablation.
 17. The device of claim 1, whereinthe end probe comprises: the plurality of electrodes bonded to the firstexpandable membrane and configured to deliver Radio-Frequency energy totissue of the pulmonary vein and sense temperature at each electrode.18. The device of claim 1, wherein the plurality of electrodes isoriented circularly to circumferentially contact with an ostia of thepulmonary vein.
 19. The device of claim 1, wherein the device is furtherconfigured for using the plurality of electrodes for visualization,stimulation, recording, and ablation.
 20. The device of claim 1, whereineach electrode is configured so an amount of power delivered to eachelectrode is controlled independently.